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ATTENUATED FAMILIAL
ADENOMATOUS POLYPOSIS (AFAP)
The experience of the Colorectal Cancer Study Group
of the University of Modena and Reggio Emilia
M. Ponz de Leon, F. Domati, L. Roncucci, G. Rossi, R. Sassatelli, P. Benatti, C. Di Gregorio,
M. Pedroni, S. Maffei, D. Nozzi, L.Reggiani Bonetti, E. Borsi, C. De Gaetani, A.Merighi
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AUTHORS
Maurizio Ponz de Leon
Professor of Internal Medicine, Dipartimento di
Medicine e Specialità Mediche, Università di Modena e
Reggio Emilia (Italy)
Federica Domati
Research Fellow, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Luca Roncucci
Associate Professor of Internal Medicine, Dipartimento
di Medicine e Specialità Mediche, Università di Modena
e Reggio Emilia (Italy)
Giuseppina Rossi
Research Fellow, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Romano Sassatelli
Endoscopist, Endoscopy Unit, Reggio Emilia Hospital
(Italy)
Piero Benatti
Aggregate Professor of Internal Medicine, Dipartimento
di Medicine e Specialità Mediche, Università di Modena
e Reggio Emilia (Italy)
Carmela Di Gregorio
Pathologist, Pathology Unit, Carpi Hospital (Italy)
Monica Pedroni
Chief Technician, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Stefania Maffei
Research Fellow, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Daniela Nozzi
Research Fellow, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Luca Reggiani Bonetti
Pathologist, Dipartimento di Patologia
Università di Modena e Reggio Emilia (Italy)
Enrica Borsi
Research Fellow, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Carmela De Gaetani
Pathologist, Dipartimento di Patologia
Università di Modena e Reggio Emilia (Italy)
Alberto Merighi
Endoscopist, Dipartimento di Medicine e Specialità
Mediche, Università di Modena e Reggio Emilia (Italy)
Umana,
Umana,
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Addresses of the Study Group:
• Struttura Complessa di Medicina 1, Dipartimento di Medicine e Specitalità Mediche,
Policlinico, Via del Pozzo 71, 41100 Modena (Italy)
• Servizio di Anatomia Patologica, Ospedale di Carpi, Via G. Molinari 2, 41012 Carpi
(Modena)
• Struttura Complessa di Anatomia Patologica, Dipartimento di Servizi Diagnostici, di
Laboratorio e di Medicina Legale, Policlinico, Via del Pozzo 71, 41100 Modena
Telephones:
M.Ponz de Leon
+39 059.4222269
Secretary (G.Rossi)
+39 059.4224715
P.Benatti
+39 059.4225895
L.Roncucci
+39 059.4224052
C.Di Gregorio
+39 059.659480
C.De Gaetani
+39 059.4224816
Fax:
Secretary (MO)
+39 059.4222958
Anatomia Patologica (MO) +39 059-4224820
Anatomia Patologica Carpi +39 059-659469
E-mail:
M.Ponz de Leon
[email protected] ([email protected])
P.Benatti
[email protected]
L.Roncucci
[email protected]
C.Di Gregorio
[email protected]
C.De Gaetani
[email protected]
Website:
www.tumoricolorettali.unimore.it
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CONTENTS
PRESENTATION
Page
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ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP)
Page
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Introduction and Definition
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Diagnosis, Clinical Features, Morphology
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Extracolonic Manifestations
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Molecular Biology and Genotype-Phenotype Correlations
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Surveillance and Treatment: Surgery versus Endoscopy
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Genetic Counseling
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Conclusions
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References
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DESCRIPTION OF FAMILIES WITH ATTENUATED FAMILIAL
ADENOMATOUS POLYPOSIS OBSERVED IN MODENA BETWEEN
1984 AND 2009
Page
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SUMMARY TABLES OF THE MAIN RESULTS OBSERVED IN THE
27 FAMILIES WITH AFAP
Page
97
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PRESENTATION
After the volumes on Lynch syndrome (2007) and Familial Adenomatous Polyposis
(2008), in 2009 the Colorectal Cancer Study Group of the University of Modena and Reggio
Emilia presents a volume which summarizes the experience with Attenuated Familial
Adenomatous Polyposis (AFAP).
The senior members of the Group initiated to study Hereditary Colorectal Neoplasms
in 1983, when families with clinical features of Familial Adenomatous Polyposis (FAP) and
Lynch syndrome were observed and characterized. While Lynch syndrome was virtually
unknown, FAP had already been described by almost 100 years; yet the syndrome was still
poorly understood in Italy, and clinical experience limited to a few centers. The disease had
been studied mainly in the United Kingdom (where a Polyposis Registry was instituted
since 1925, at St. Mark’s Hospital, London) and in the United States, but in many other
European countries the knowledge on FAP was as limited as in Italy. In 1985, experts of
several countries constituted the “Leeds Castle” Polyposis Group (from the place of the first
meeting, in Kent, U.K.) with the purpose of promoting the research on colorectal polyposis
(FAP and related syndromes). And this is what happened, since in those years (1985-1995)
there were several advancements, including the definition of extracolonic manifestations,
the development of chemoprevention and, above all, the identification of APC gene. In
1998, the Leeds Castle Group joined with the International Study Group on Lynch
syndrome, giving origin to the InSiGHT, the Association which gathers all researchers
interested in familiality and clinical genetics of tumors of the digestive organs.
The Colorectal Cancer Study Group of the University of Modena and Reggio Emilia
played an active role in this long period of rewarding and fruitful scientific activity.
Moreover, in the years Ninety of the XX century the Group was among the promoters of the
constitution of AIFEG (Associazione Italiana per lo studio della Familiarità ed Ereditarietà
Gastrointestinale), the Society which represents Italian researchers interested in the study of
Polyposis and Lynch syndrome.
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Along these years, the Study Group continued in the scientific way traced at the
beginning of its activity, that is, identification, management, biological and molecular
characterization of Hereditary Colorectal Cancer Syndromes. The institution, in 1984, of a
specialized colorectal cancer Registry, in the Health Care District of Modena, was of great
help in reaching these objectives. At present, 64 families with clinical features of FAP have
been identified (41 of which with constitutional mutations in either APC or MutYH genes),
34 families with Lynch syndrome (all with germline mutations in either MSH2, MLH1 or
MSH6 genes), 32 families with clinical HNPCC (i.e., clinical features of Lynch syndrome
but without documented constitutional mutations), and 6 families with clinical features
suggestive of Peutz-Jeghers syndrome.
The first part of this volume deals with general aspects of AFAP, such as definition,
molecular biology, clinical features and management. In the second part the individual
families identified between 1984 and 2009 are illustrated in details, with a schematic
genealogical tree, a list of the main clinical data of affected patients, a concise family
history and the results of biomolecular tests. In the last part of the volume summary tables
of the main data are presented.
The objective of the volume is two-fold. First, to illustrate our group of patients and
families, pointing out the main clinical and biological challenges related to the diagnosis of
AFAP. Second, to make accessible to physicians – both specialists and family doctors – a
topic which remains poorly defined and difficult to manage, especially for its genetic basis
and the consequent implications for family members of the proband.
In 2005 a screening campaign against colorectal tumors was initiated in Region
Emilia-Romagna. One of the effects of this Public Health intervention was to alert
physicians (and the general population) on the clinical, epidemiological and social relevance
of colorectal neoplasms. It seems to us appropriate, with the present volume, to illustrate a
rare but particularly interesting clinical entity which represents an ideal model for the study
of colorectal tumorigenesis.
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Finally, we would like to express our gratitude to all individuals – doctors and
patients – who offered their help in the study of Attenuated Polyposis and, thus, in the
collection and analysis of the data reported in this volume. In particular, we would like to
thank:
Dr.ssa Alessandra Viel, Centro di Riferimento Oncologico, Aviano, Pordenone
Prof. Maurizio Genuardi, Genetica Medica, Università di Firenze
Dr.ssa Tiziana Venesio, Centro Oncologico, Candiolo, Torino
Dr.ssa Liliana Varesco, Istituto Nazionale per lo Studio dei Tumori, Genova
Prof. Francesco Tonelli, Chirurgia Generale, Università di Firenze
Prof. Giovanni Lanza, Anatomia Patologica, Università di Ferrara
and their collaborators, with whom we shared at least 20 years of continuous and
enthusiastic investigation, and we continue to collaborate.
The Authors
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ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP)
INTRODUCTION AND DEFINITION
Familial Adenomatous Polyposis (FAP) is characterized by the presence of at least
100 adenomatous lesions of the large bowel, several extracolonic manifestations and an
autosomal dominant type of genetic transmission (1, 2). The disease is caused by
constitutional mutations in the APC gene (for Adenomatous Polyposis Coli) (3, 4), and, to a
lesser extent, by mutations of the recently identified MutYH gene (5, 6).
At variance with classic FAP, Attenuated Familial Adenomatous Polyposis (AFAP)
is characterized by the presence of < 100 synchronous adenomas of the large bowel (7, 8);
extracolonic manifestations are not so frequent as in FAP (9), and in most cases only one
individual is affected in a given family (10); moreover, the relative contribution of APC and
MutYH to the AFAP phenotype has to be defined (11). As a matter of fact, the term
“attenuated” refers not only to the number of adenomas, but also to the milder clinical
course of the disease, featured by a later onset of colorectal adenomas and carcinoma, and a
limited expression of extracolonic changes.
Lynch et al (12) and Leppert et al (13) were presumably the first to draw attention to
this new phenotype, by describing families with several adenomas and often malignancies
of the large bowel but not meeting the clinical criteria for FAP. Since then, several other
families with this attenuated form of polyposis have been reported; however, AFAP still
remains a poorly defined disease, despite the attempt to suggest precise diagnostic criteria
(14). Probably the simplest way to define the syndrome is to consider as AFAP any case
presenting with a number of synchronous adenomatous lesions of the large bowel ranging
between 10 to 99, unregarding the age of onset, the presence of constitutional mutations,
extracolonic changes and features of autosomal dominant or recessive transmission. If this
definition has the great advantage of simplicity, it should be acknowledged that in some
cases (i.e., patients with 10 to 15 adenomas) the differential diagnosis from multiple polyps
of the large bowel may be difficult, if not impossible. By the same token, in presence of 90
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to 99 adenomatous lesions the distinction between AFAP and FAP might reveal rather hard.
Molecular biology does not seem to be of help, since at variance with FAP (where
constitutional mutations are usually detected in 80 to 95% of families) germline alterations
can be identified in 30-50% of patients and families with attenuated polyposis (15).
Since the definition is unclear and no real consensus exists, incidence and frequency
of AFAP are difficult to establish. In the Dutch experience less than 10% of FAP patients
showed the attenuated phenotype (16), whereas in the large series of Friedl et al AFAP was
diagnosed in approximately 15% of FAP families (17), and even lower estimates were
reported by other studies (18). However, it is worth noting that in none of these
investigations a systematic search for Attenuated Polyposis – through endoscopic records or
data of a cancer Registry – was carried out or attempted.
At present AFAP is recognized as a distinct clinical entity, based on the presence of
attenuated clinical features as compared with FAP. Whether such distinction between FAP
and AFAP is warranted remains difficult to anticipate, since future biomolecular
investigations might reveal that the syndrome at present defined as AFAP is only part of a
larger entity based on APC and MutYH constitutional alterations. Moreover, the possible
involvement of other genes implicated in the mechanisms of DNA base excision repair in
inducing the AFAP phenotype cannot be excluded (19).
DIAGNOSIS, CLINICAL FEATURES, MORPHOLOGY
Because of uncertainties in defining the syndrome, not all series which appeared in
the literature respected the upper limit of 90-100 adenomas in the large bowel, and the lower
limit of 10 lesions was even less taken into account. For instance, in a large series published
in 1998 (20), the mean number of adenomas was 44, but the range between 1 and 500. The
Dutch Polyposis Registry recently defined AFAP as follows: 1) at least two first-degree
relatives with 10-99 colorectal adenomas diagnosed after the age of 30 years; 2) one patient
with 10-99 adenomas diagnosed after the age of 30 years plus a first-degree relative with
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colorectal cancer and a few (< 10) adenomas; 3) no family members with “classic” FAP (>
100 adenomas) before the age of 30. Applying this definition, 25 out of 315 FAP families
(8.0%) met the clinical criteria for attenuated polyposis (21).
According to some authors, the majority of patients with AFAP show a prevalent
proximal distribution of adenomas (i.e., from the cecum to the splenic flexure), and these
are often of the flat type (22, 23). However, this does not seem to be a general rule, and in
many patients the lesions are distributed exclusively, or predominantly, in the left colon, as
it occurs in classic FAP (24). Some studies reported a tendency to spearing the rectum from
adenomas in AFAP individuals (25).
As far as the age of onset of adenomas is concerned, this is usually delayed in AFAP
when compared with the pattern observed in FAP. Thus, Scott et al reported that individuals
with Attenuated Polyposis were diagnosed, on average, more than 15 years later than FAP
patients (15). Among symptoms leading to diagnosis, rectal bleeding and abdominal
discomfort are by far the most frequent (26). Owing to the small size of many AFAP
families, and the prevalence of solitary cases, diagnosis for screening is less frequent than in
FAP (27). In most series, the mean age of adenoma development ranges between 40 and 50
years (21, 28), and in approximately half of the patients cancer is already present at
diagnosis. In most series, Attenuated Adenomatosis Coli affects the two sex at the same
extent, a feature which is consistent with autosomal transmission; however, there are reports
of a striking gender effect (with female preponderance) in AFAP patients (28, 29, 30).
Histologically, colorectal adenomas which develop in AFAP do not seem to be
different from sporadic lesions as well as from polyps observed in profuse polyposis.
Tubular or tubulovillous adenomas with low, medium or severe dysplasia (low and high
grade) are the most frequent pathological findings in these patients. However, according to
some authors flat lesions seem particularly frequent in AFAP (22, 23, 31), and this may
complicate diagnosis and follow-up (32). In addition, Boporai et al (33) recently reported
the frequent occurrence of hyperplastic polyps and of sessile serrated adenomas especially
in the subgroup of individuals with constitutional mutations in the MutYH gene, thus
suggesting that these types of polyps could be associated causally with deficiency of
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MutYH function and, in turn, that different morphological pathways might exist between
APC-gene and MutYH-gene related polyposis.
EXTRACOLONIC MANIFESTATIONS
In classic FAP extracolonic manifestations are usually observed in almost all
families, and in some cases they can alert the physician on the existence of the syndrome. In
Attenuated Polyposis there are several reports of extracolonic changes, however, their
frequency seems lower than in FAP; what remains unclear is whether this low incidence
reflects a biological feature of AFAP, or should be attributed to less attention in searching or
reporting alterations which are not limited to the large bowel.
Thus, there is very limited information on the frequency of Congenital Hypertrophy
of the Retinal Pigmented Epithelium (CHRPE) in patients with Attenuated Familial
Polyposis (34); similarly, other common features of FAP such as osteomas, supernumerary
teeth, epidermoid cysts, hepatoblastoma and thyroid carcinoma have been reported only
occasionally. The frequency of desmoid tumors is in the order of 10-15% of all patients (and
families) with FAP, but their incidence in AFAP has not been determined, though several
authors reported an increased risk of desmoids in some families with the attenuated
phenotype and specific APC constitutional mutations (35, 36). There are also reports of
families with a marked inheritance of desmoid tumors (“Hereditary Desmoid Diseases”,
according to some authors) associated with clinical features of Attenuated Polyposis (37,
38).
Glandular polyps of the stomach and duodenal adenomas are undoubtedly the most
frequent extracolonic manifestations observed in FAP as well as in AFAP. However, if
there is a general consensus on a reported frequency of gastric lesions in about 50% (though
much higher in Japanese series) (39, 40), and of duodenal adenomas in 90-100% of patients
with classic FAP, the reported frequency of these lesions appears to be lower in AFAP, and
with conflicting results. Thus, in one series gastroduodenal lesions (mostly glandular polyps
of the fundus and antrum) were found in nearly 70% of patients with Attenuated Polyposis
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(41), while other authors reported much lower rates (42, 43). Upper gastroduodenal
malignancies (periampullary lesions in most cases) have been detected in only few patients
with AFAP (44, 45).
MOLECULAR BIOLOGY AND GENOTYPE-PHENOTYPE CORRELATIONS
The AFAP phenotype can be associated with constitutional mutations of at least two
genes: APC and MutYH. This means that in some cases the disease is transmitted through
an autosomal dominant model (APC), while in other cases through a recessive type of
inheritance. How many cases of AFAP should be attributed to APC alterations and how
many to MutYH changes is still a matter of concern, although both genes play an important
role, and the prevalent attitude is to consider two forms of polyposis, one associated with
APC (APC-related FAP) and one with MutYH (MutYH related FAP, more simply, MAP)
(46). It is likely, however, that germline alterations of other genes contribute to the AFAP
phenotype, including genes of base-excision repair and those of DNA mismatch repair
machinery (47, 48). Finally, owing to the frequency of adenomatous polyps in the general
population and to the lack of stringent criteria for defining AFAP, it is also possible that in a
given fraction of all cases the disease might be due to environmental factors, presumably
inducing somatic DNA alterations in genes crucial for cell replication and differentiation
(49, 50).
APC Related AFAP
The APC gene is located on chromosome 5q21, and is constituted by 2,843 codons in
15 exons. APC functions as a tumor suppressor gene and encodes for a 300 KDa protein
which interacts with β-catenin. In absence of APC (usually as a consequence of truncating
mutations), the binding to β-catenin does not occur, β-catenin accumulates in the cytoplasm
and binds to specific transcription factors, thus altering the expression of various genes
influencing cell proliferation, differentiation and apoptosis (51, 52). This proliferative
response may represent the first step toward cancer development.
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In individuals with the AFAP phenotype several mutations have been identified in
the APC locus. It is commonly assumed that the disease is due to mutations in the extreme
portions of the gene, 5’ or 3’ ends. However, from the available literature it seems that these
alterations are not clustered in a specific DNA segment of the gene, but encompass exons 3,
4, 5, 6, 9 and a large fraction of exon 15 (approximately from codon 1000 to 3000) (53, 54).
No clear and well established genotype-phenotype correlations have been revealed.
Thus, number of polyps in the large bowel, presence of extracolonic manifestations and
morphologic features of adenomas in APC-associated AFAP do not seem to be related to
specific germline alterations. This is not surprising, since in FAP patients correlations
between type of mutation and expressed phenotype could be established only in large
groups of individuals, while the phenotype cannot be predicted in individual subjects. In
addition, several observations showed a marked phenotypic variability in patients carrying
the same APC mutation (55, 56).
The prevalence of APC mutations among individuals with clinical features of
Attenuated Polyposis remains poorly defined. In a recent study, Nielsen et al (21) reported
that approximately 1/3 of their AFAP patients were positive for APC mutations; however,
these families were selected on the basis of stringent clinical criteria, concerning not only
the number of colorectal adenomas, but also age at diagnosis and the presence of affected
first-degree relatives. With a different and less stringent definition of AFAP, a lower
prevalence of mutations should be expected.
MutYH Related AFAP
The MutYH gene (previously known as MYH) encodes for a glycosylase involved in
the base excision repair caused by oxidative damage to DNA (57); the gene, located at
chromosome 1p32-34, is deleted in several human malignancies (58). In 2002, Al Tassan et
al reported the presence of biallelic MutYH mutations in a family with several members
affected by multiple colorectal adenomas and carcinoma (5). Further investigations revealed
that homozygous or compound heterozygous mutations of MutYH could be detected in 20
to 30% of AFAP patients and in approximately 10% of classic FAP cases (59, 60). Thus,
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after nearly 20 years from the discovery of APC, a second gene specifically associated with
the adenomatosis phenotype was identified; moreover, the studies showed an unsuspected
role of the base excision repair system in genetically determined colorectal neoplasms.
In Western countries, the two missense mutations Y165C and G382D (Y179C and
G396D according to other authors) account for the large majority of disease-causing
alterations (61), while in some Eastern populations the nonsense E466X mutation seems to
be the most frequent (62). In accordance with an autosomal recessive type of genetic
transmission, biallelic mutations are required for the development of polyposis or cancer;
indeed, no unaffected carrier of biallelic MutYH mutations has been identified, thus
suggesting a high penetrance of the trait (63). It is still undefined whether the heterozygous
condition carries an increased risk of adenomas or carcinoma in the large bowel or other
organs.
Immunohystochemical studies indicated that neoplasms developed in MutYHassociated polyposis show disappearance of staining from the nucleus, and segregation of
immunoreactivity in the cytoplasm, thus suggesting a possible role of this technique in the
screening for individuals at risk of MAP (64). Other authors, however, were unable to find
out distinctive pathological features of the immunohistochemical pattern which could
predict the presence of MutYH mutations in colorectal cancer (31). Recent studies
suggested interesting genotype-phenotype correlations in MAP. Thus, Nielsen et al (65)
showed that patients with biallelic G396D (or compound G396D/Y179C) mutations
presented later with clinical features of polyposis and had a lower risk of developing
colorectal cancer than patients with homozygous Y179C mutations. It seems therefore that
some alterations can be associated with a more severe phenotype and clinical course, while
other mutations with a relatively milder disease.
At variance with APC, whose role in AFAP is not precisely defined, several studies
indicated that MutYH is mutated in 20 to 40% of all patients and families with clinical
features of Attenuated Polyposis (30, 66, 67). Thus, in families with suspicion of recessive
inheritance (i.e., lack of vertical transmission of the trait cancer or polyposis) or when
neoplasms show evidence of DNA excision repair damage – such as G
T transversions
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at codon 12 of the K-ras gene (68) – molecular studied should begin with a detailed
sequence analysis of the MutYH gene.
SURVEILLANCE AND TREATMENT: SURGERY VERSUS ENDOSCOPY
At variance with FAP – in which surveillance and treatment follow precise guidelines
that have been improved over time (69) – no consensus exists on the management of
Attenuated Polyposis and, consequently, the clinical approach to the disease remains largely
empirical.
Mutation analysis of APC and MutYH genes assumed considerable importance in the
most recent years, not only for being of help in differentiating between FAP and AFAP, but
also for excluding the presence of other inherited cancer syndromes – such as Lynch
syndrome (70) or its variant Muir-Torre syndrome (71) – that may in some cases mimic
AFAP. For subjects who test positive for APC or MutYH (biallelic) mutations associated
with
clinical
features
of
AFAP,
baseline
colonoscopy
together
with
esophagogastroduodenoscopy should be carried out at the time of genetic testing or by the
age of 14-16 years; in case of negative results, the investigation should be repeated after 2-3
years and then at regular intervals of time, since late appearance of adenomas is frequent
(72). It should be noted however that in most series some 30 to 50% of patients may result
negative for constitutional mutations and, consequently, management should be based only
on clinical findings (73).
The main clinical decision to be taken in patients with Attenuated Polyposis is the
choice between endoscopic or surgical approach to the disease. In absence of well defined
guidelines, a purely empirical approach could be traced as follows. Patients with clinical
features of AFAP, but with a number of polyps which can be removed through endoscopy
should undergo polypectomy with continued yearly surveillance. It is important to analyze
all removed lesions, since the presence of severe dysplasia in one or more adenomas might
change the conservative approach into a more radical treatment. Patients with adenomatous
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lesions too numerous to be removed endoscopically, or for whom endoscopic surveillance is
not possible (low compliance), should be considered for surgical management (7, 74).
Patients with Attenuated Polyposis are at increased risk of developing colorectal
cancer when compared with the general population; however, the exact risk is difficult to
calculate, and from the available observations does not seem as “absolute” (that is, nearly
100%) as for FAP patients. It follows that indications for prophylactic colectomy differ
between the two conditions. First of all, many AFAP patients are treated lifelong with the
sole endoscopic approach, especially when up to 20 polyps are present in the large bowel
and no severe dysplasia is observed at histology (74, 75). Second, when the excessive
number of polyps hampers the complete endoscopic removal but the rectum is spared from
lesions (or it shows a few small lesions that can easily be removed), subtotal colectomy and
ileorectal (or ileosigmoid) anastomosis are usually carried out, instead of the technically
more difficult proctocolectomy with ileoanal anastomosis and J pouch (76). In case of this
choice, it is quite obvious that the rectal stump should require continuous surveillance,
owing to the high risk of newly developed lesions (77). Finally, when multiple adenomas
are clustered in a single segment of the large bowel – especially in the proximal intestine –
segmental resection or hemicolectomy may be valuable options (78), providing of course
that the patient is willing to undergo close endoscopic surveillance of the remaining large
bowel.
Treatment and surveillance can also be influenced by recent advancements in
molecular biology. In a collaborative investigation, Bulow et al. (76) recommended to
execute colectomy and ileorectal anastomosis (but not ileoanal anastomosis) in FAP or
AFAP patients with APC constitutional mutations at codon 0-200 or after codon 1500, at
the two extremes of the gene. In contrast, according to some authors, mutations in the
central zone of the gene (around codon 1309), usually associated with a severe phenotype
and profuse polyposis, would benefit of proctocolectomy and ileoanal anastomosis (79, 80).
In a recent study, Nielsen et al identified biallelic MutYH mutations associated with a
severe phenotype (Y179C), thus suggesting that even for MutYH gene alterations
surveillance and management (of AFAP patients) might be somehow guided by the
molecular findings (65).
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Other investigations suggested that certain drugs – especially nonsteroideal antiinflammatory compounds – may play a role in reducing number or dimensions of adenomas,
especially in classic FAP (81, 82). It should be noted, however, that most studies showed
incomplete polyp regression, and over short follow-up periods (83). Sulindac, Celecoxib
and Rofecoxib (the second and third COX-2 inhibitors) were the most effective in reducing
the polyp burden. There is little or no information on the possible role of these drugs in
Attenuated Polyposis. Two major factors, however, should be taken into account. First,
there is evidence of colorectal cancer occurrence during attempts to induce polyp regression
through the use of anti-inflammatory compounds (84). Second, recent observations reported
an increased cardiovascular risk and thrombotic effects among patients treated with COX-2
inhibitors in adenoma chemoprevention trials (85), thus raising some concerns about the
appropriate use of these new drugs.
Treatment of upper gastrointestinal lesions is difficult in classic FAP and may be
complex also in Attenuated Polyposis, at least in individual cases (86). Most physicians
recommend gastroduodenoscopy at regular intervals of time for AFAP patients, and gastric
polyps (usually glandular or hyperplastic lesions) or duodenal adenomas may precede, in
some patients, the appearance of colorectal tumors (87). As in the case of FAP, optimal
treatment and surveillance of upper gastrointestinal lesions, and the possible advantage of
chemoprevention (with nonsteroideal anti-inflammatory drugs, Ursodeoxycholic acid or
other chemical compounds) remain still undefined (88).
GENETIC COUNSELING
In general terms, with genetic counseling the physician tries to acquire all relevant
information concerning a given individual, his (or her) family, and the disease – presumably
genetic – object of counseling, In a successive phase the same physician (a geneticist, a
gastroenterologist, an internist or the family doctor) suggests a given strategy, which may
imply the execution of genetic tests or other clinical examinations, changes of diet and lifestyle, as well as medical or surgical interventions.
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In Attenuated Familial Adenomatous Polyposis genetic counseling follows in general
terms the same guidelines adopted from many years for classic FAP; however, while in FAP
germline mutations can be detected in 80-90% of patients with the typical phenotype (89),
in AFAP the fraction of positive families is in the order of 50% or less, at least in most
series (21). Moreover, many families present as single cases, especially when constitutional
mutations are not detectable, while in classic FAP segregation of the deleterious tract can be
followed in most families through various generations (90). As already discussed, two genes
– APC and MutYH – have been associated with the AFAP phenotype, but with different
types of genetic transmission.
Genetic counseling in APC-associated AFAP
In APC-related AFAP genetic counseling starts with a detailed description of the
pedigree, usually through the proband. In most AFAP cases the nuclear pedigree will
contain all relevant information; only few cases usually require the extension of the family
tree to second and third degree relatives (as in classic FAP). When possible, cases of cancer
or polyposis should be verified by clinical charts, histological reports or other certificates. In
tracing genealogical trees, conventional symbols are used to identify the proband (arrow),
the sex (square for man, circle for woman), death of the patient (diagonal bar), generations
(latin numbers), and single components of a sibship (arabic numbers); horizontal and
vertical lines join husband and wife, siblings and offsprings. There are not conventional
symbols for indicating the diseases. The symbols used in the present volume are
indicated inside the cover.
In the clinical suspicion of AFAP, genetic testing (i.e., search for constitutional APC
mutations) should initially be proposed to the proband; if a deleterious mutation is detected,
the test is offered, as an option, to other family members at risk identified through the
pedigree. It should be noted, and emphasized, that the decision to undergo genetic testing is
strictly personal, should be discussed with the patient and requires a written formal consent
(91). It is entirely possible, and should not surprise the physician, that a certain number of
19
high-risk individuals show indifference or even suspicion towards genetic testing; these
subjects – who might be defined “fatalistic” – probably believe, or suppose, that to became
aware of a given predisposition towards diseases (or a specific disease) might alter their
psychological equilibrium, which sometimes is reached and maintained with difficulty. In
these cases the genetic counselor should not exert any pressure, but just limit his (her)
contribution to a correct information.
In gene carriers within typical FAP families the first colonoscopy is usually
suggested at puberty, when adenomas begin to appear in most patients. Presumably the
same recommendation holds true for AFAP, in which however a later appearance of polyps
can be expected. Within a few years gastroduodenoscopy should be executed, in order to
find out gastric or duodenal lesions. In solitary cases (i.e., only one affected member), the
proband’s offsprings carry a 50% risk to be affected (in accordance with the autosomal
dominant type of transmission), and genetic testing should be proposed.
When in a given family no APC mutations are identified, then genetic testing is
unable to detect constitutional alterations despite the presence of a phenotype consistent
with AFAP. This might be due to several factors, including: a) procedural errors (which are
always possible), b) involvement of other genes, especially MutYH, c) truly sporadic cases
of AFAP, d) multiple adenomas of the large bowel which mimic AFAP. When no APC (or
MutYH) mutations are detected in a given family or individual, the genetic test loses any
predictive value, and cannot identify cases at risk of polyposis. In these subjects – who
probably represent the larger fraction of AFAP – first-degree relatives of the proband should
be followed-up only on a clinical basis, starting with endoscopic surveillance at puberty and
continuing lifelong at regular intervals of time (92, 93).
Genetic counseling in MutYH-associated Polyposis (MAP)
According to some series, nearly one third of all Attenuated Polyposis can be
attributed to biallelic constitutional mutations in the MutYH gene (59, 60). At variance with
APC, MutYH recognizes an autosomal recessive type of transmission, thus, clinical
20
manifestations appears only in case of biallelic (homozygous or compound heterozygous)
mutations. In most instances, affected individuals have healthy parents, though
heterozygous carriers of the mutation, and similarly unaffected will result the offsprings.
The pattern of transmission is markedly different from that of APC-related polyposis: no
“verticality”, but presence of affected individuals in a single generation or sibship. By
extending the genealogical tree, other affected individuals can be identified, but with
intervals of unaffected generations. As in all recessive conditions, the transmission of
MutYH mutations is difficult to recognize when compared with APC-positive families,
either for the “horizontal” pattern of transmission, or for the small size of most modern
families. Since the risk that an individual with heterozygous parents results affected is in the
order of 25% (1 in 4), it follows that in the majority of cases AFAP associated with MutYH
mutations will appear as sporadic, without any family history suggestive of a genetic defect.
Main recommendations concerning diet and style of life
Carriers of constitutional mutations of the APC or MutYH genes are at increased risk
of developing adenomatosis and cancer of the large bowel. The risk approaches 100% for
FAP patients, while for Attenuated Polyposis it is still undefined, though much higher than
that of the general population (94). A similar risk can be expected for AFAP individuals in
whom germline alterations cannot be detected. Progression from normal appearing mucosa
to adenomas and cancer depends on several factors, including, presumably, the type of
mutation, the role of modifier genes (95), and the possible interaction between genotype and
several environmental agents (96).
As already discussed, the main recommendations for gene carriers (and, more in
general, for individuals at risk) concern screening and endoscopic surveillance of the large
bowel, and, after surgery, the rectal stump and ileal reservoir; moreover, a careful follow-up
of the upper gastrointestinal tract is also suggested. The ongoing clinical trials should
provide an answer to the possible role of chemoprevention, especially with Cox-2 inhibitors
(97).
21
At present there is no evidence that diet and style of life can be of help in influencing
the clinical course of patients with FAP or AFAP phenotypes. However, there is some
consensus on the relevance of some protective or risk factors in the pathogenesis of
colorectal neoplasms, despite the poor reproducibility of several observations (98, 99).
Although most of the studies refer to sporadic tumors, rather intuitively the same
implications might be relevant also for individuals with inherited colorectal neoplasia, such
as Lynch syndrome, FAP or Attenuated Polyposis. Following this line of reasoning, it is
likely that at least the following suggestions on diet and style of life might be given to
patients with FAP or AFAP:
1. It is important to avoid a fully sedentary life, especially for those individuals whose
job activity does not imply physical exercise (the large majority of the population, at
present);
2. Similarly relevant is to reach and maintain an ideal body weight, avoiding
overweight and obesity;
3. We would suggest to quit cigarette smoking, and to limit the ingestion of alcoholic
beverages (100, 101);
4. As far as the diet is concerned, the situation is even more complex (102, 103).
However, the main suggestions remain the following:
-
to enrich the diet of dry fiber, such as bran;
-
to increase the consumption of fruit and vegetables;
-
to limit the ingestion of meat and animal fat.
22
CONCLUSIONS
Attenuated Familial Adenomatous Polyposis is a relatively new clinical entity
described approximately 20 years ago (12, 13) and since then actively investigated.
However, AFAP remains poorly defined, and there are still concerns whether or not it
represents a disease, or a syndrome, entirely separated from FAP, on one extreme, and from
Multiple Adenomas of the large bowel on the other extreme. AFAP is characterized by a
milder phenotype when compared with classic FAP, not only for the absolute number of
adenomas, but also regarding the age of onset of colorectal neoplasms (both benign and
malignant) and the frequency of extracolonic manifestations. Moreover, although the same
genes (APC and MutYH) seem to be involved, some 30 to 50% of AFAP patients, or even
more, remain without a genetic diagnosis (59, 60).
The main difficulty with AFAP is a proper definition of the disease, since clinical
criteria have not been defined, and are difficult to define. If we apply strict clinical criteria,
taking into account not only the number of adenomas, but also the age of onset of polyps
and familial aggregation of neoplasms, then we could miss many cases. On the other hand,
by accepting a simple definition of AFAP – such as the presence of less than 100 adenomas
in the large bowel, unregarding age of onset and family history – it is likely that some
patients with sporadic multiple polyps (104) could be included among AFAP cases. In fact,
to distinguish AFAP from the group of multiple adenoma patients is extremely difficult on a
clinical ground, owing to the similar phenotypes, and the possible presence of a family
history of polyps and cancer in both categories of patients. It should be noted, however, that
the diagnosis of FAP is based only on the phenotype (> 100 synchronous adenomas of the
large bowel), and does not take into account the age of onset of the lesions or the presence
of “verticality” (105). By analogy, therefore, the definition of AFAP might be based mainly,
if not exclusively, on the phenotype of the proband.
In the present volume we selected families on the basis of a simple definition of
AFAP: the presence in the large bowel of a number of synchronous adenomas in the range
10 to 99. We considered this definition as the most appropriate, especially in analogy with
the accepted clinical definition of FAP. This does not mean that age of onset of adenomas
23
(or cancer), dominant or recessive type of transmission, and presence of constitutional
mutations are not important; however, some of these parameters could be viewed as criteria
of exclusion for many AFAP patients. Again, by analogy with the well defined classic
Polyposis, up to 30% of typical FAP patients appear as “solitary cases”, and this means
without a family history, often with a late age of onset, and in some cases without a
molecular diagnosis (106).
Unavoidably, the choice to adopt a rather “loose” definition of AFAP renders the
clinical condition extremely heterogeneous. It is likely therefore that AFAP patients
described in the present volume reflect a spectrum of diseases which spans from purely
genetic cases of FAP and other Hereditary Cancer syndromes to sporadic multiple
adenomas of the large bowel.
The other relevant and unsettled aspect of AFAP is treatment. On the basis of clinical
findings, we should expect a better prognosis in AFAP compared to classic FAP; however,
evidence of this contention if lacking, and, consequently, several uncertainties remain on the
choice of the optimal approach. Owing to the high risk of cancer, and to the possibility of
overlooking neoplasms during surveillance (mainly for the poor compliance of many
patients) many authors favor prophylactic colectomy, usually with ileorectal anastomosis,
and consider surgery as the optimal therapy (76). However, an increasing number of AFAP
patients are managed through endoscopy, especially when the polyps are not too numerous.
More observations and, possibly, controlled clinical trials are required to define standard
guidelines of treatment in Attenuated Polyposis.
24
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36
DESCRIPTION OF THE FAMILIES WITH ATTENUATED FAMILIAL ADENOMATOUS
POLYPOSIS OBSERVED IN MODENA BETWEEN 1984 AND 2009
In more than 25 years of continuous activity, the Colorectal Cancer Study Group of the
University of Modena and Reggio Emilia examined several hundred of pedigrees, either of patients
diagnosed through the local Colorectal Cancer Registry or individuals addressed to the Institution
from other Provinces and Regions.
In 28 of these pedigrees (often single individuals) features of AFAP were observed in the
proband and, in some cases, in other members of the family. In particular, a total of 10 to 99
synchronous adenomas in the large bowel. These cases have been classified as “Attenuated Familial
Adenomatous Polyposis (AFAP)”. In 5 of these families constitutional mutations of the APC gene
(n. 3) or MutYH gene (n. 2) were detected.
For each family a genealogical tree has been traced, as it appeared at the last visit (usually
between 2007 and 2009). Below the pedigree there is a table which summarizes, for that specific
proband and family, the most relevant clinical data. The second page shows a schematic family
history, that reports the most significant diseases of the proband and other affected family members.
Emphasis has been given to benign and malignant neoplasms of the large bowel. When information
was scanty, lacking or incomplete, this has been indicated in the text.
Finally, in a box at the base of the second page we described the results of genetic testing
carried out on constitutional DNA (i.e., search for APC and MutYH mutations).
37
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N.1
2
1
I
K colon 78
a 86
1
II
AFAP +
K colon 65
1
2
3
III
a 55
a 43
a 49
IV
a 31
a 18
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-1
AFAP +
Cancer of the
Cecum
65
_
1st operation
Subtotal colectomy
and ileorectal
anastomosis (IRA)
(1989)
2nd operation
Proctectomy
and Ileostomy
(Recurrence, 1994)
Mutations
(APC/MutYH)
Not tested
38
History of the proband and the family.
The proband (II-1) underwent colonoscopy in 1989, at the age of 65 years, because of abdominal
pain and bloating. The investigation showed diffuse polyposis especially in the transverse and
ascending colon, with polyps ranging from 2-3 mm to 4 cm in diameter. A malignant lesion
occupied the cecum. After a few days, the patient was operated on of subtotal colectomy and IRA.
At anatomical examination a total of 78 adenomas with different degrees of dysplasia could be
observed in various segments of the large bowel, and an adenocarcinoma (Stage III TNM, Dukes’
C) of the cecum. After the operation, the patient did not undergo chemotherapy; he was reluctant to
be followed by rectoscopy at regular interval of time. In 1994 he noticed rectal bleeding, and a
neoplasm of the rectal stump was diagnosed. The patient was operated on of proctectomy and
permanent ileostomy. After the operation the patient did not complain other troubles related to the
disease. He died in 2003, at age 79, owing to complications of pneumonia.
In the family, the father of the proband was operated on at the age of 78 years for cancer of the large
bowel, and died after a few months. No other cases of neoplasms were referred. The 3 daughters of
the proband refused (and continue to refuse) any investigation.
Molecular characteration
No genetic test has been carried out.
39
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 2
1
2
I
a 72
a 69
1
II
AFAP 35
1
III
a 11
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-1
AFAP
35
_
_
Mutations
(APC/MutYH)
Negative
40
History of the proband and the family.
After several years of abdominal discomfort attributed to “irritable bowel”, the proband underwent
colonoscopy in 2002, at the age of 35 years. The endoscopic description was rather vague
(“numerous polyps” in various segments of the large bowel; the number was less than 100),
however, 30 polyps were removed and analyzed. The histological examination showed tubular and
tubulovillous adenomas with low-grade dysplasia. The search for extracolonic manifestations was
negative. From 2002 to 2007 the patient was treated with Celecoxilb (200 mg x 2). Various
endoscopic controls documented the reoccurrence of 1 to a few small polyps, which were removed
and analyzed (usually tubular adenomas with low-grade dysplasia). At the last control (April 2008),
1 small adenoma and two hyperplastic polyps were observed and removed.
No other member of the family showed features of polyposis.
Molecular characteration
No constitutional alterations of the APC and MutYH genes were detected.
41
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 3
2
1
I
a 80
1
a 84
2
3
4
II
a 61
AFAP +
K colon 49
a 58
1
2
3
4
5
a 35
a 24
a 35
a 33
a 24
a 49
6
III
a 20
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-3
AFAP +
Cancer of the
Ascending colon
49
Thyroid Cyst
Subtotal colectomy
and IRA
Negative
42
History of the proband and the family.
At the age of 49 years, the proband, II-3, complained severe and persistent abdominal pain with no
other relevant symptoms. A subsequent colonoscopy showed the presence of numerous polyps in
the large bowel and an infiltrating lesion in the ascending colon. In 2003 (age 50) the patient was
operated on of subtotal colectomy and ileorectal anastomosis. At anatomical examination a total of
22 polyps (adenomas, with various degrees of dysplasia) were detected. In the ascending colon a
Dukes C adenocarcinoma (T3N2M0) could be observed. The patient received 5 FU-based
chemotherapy for 6 months. After surgery, the endoscopic follow-up has been so far unremarkable.
No other member of the family showed features of polyposis. In particular, two out of 3 siblings (II1 and II-2) underwent colonoscopy, which resulted negative. The two offsprings of the proband (III5 and III-6) have not been tested. Both the parents of the proband (I-1 and I-2) died over the age of
80 years for causes unrelated to neoplasms.
Molecular characteration
No mutations were detected in the APC and MutYH genes.
43
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 4
1
2
I
a 79
1
a 87
2
3
II
AFAP 47
1
AFAP +K colon
43
3
2
4
5
III
a 30
a 31
a 24
a 21
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-1
AFAP
47
_
_
MutYH +
II-3
AFAP +
K Colon
43
_
Subtotal
colectomy
and IRA
MutYH +
a 18
t
44
History of the proband and the family.
The proband (II-1) underwent colonoscopy in 1998, at the age of 47 years, when she knew that the
brother had been operated on for colorectal cancer. The endoscopy showed the presence of nearly
50 small polyps scattered in the various segments of the large bowel. The lesions were subsequently
all removed, and histological examination revealed tubular adenomas with low-medium degree
dysplasia. Since then the patient underwent regular endoscopic controls with removal of the newly
developed lesions. The last two colonoscopies (2007 and 2008) were negative.
The proband’s brother (II-3) complained symptoms of abdominal discomfort in early 1998, at the
age of 43 years. An endoscopic evaluation raised the suspicion of malignant lesions in the sigmoid
colon, and the patient was operated on of subtotal colectomy and ileorectal anastomosis. At
pathology, 2 malignant lesions were present (sigmoid and splenic flexure; T3N0M0, T1N0M0),
together with 11 adenomatous polyps mainly located in the left colon. Subsequent endoscopic
controls showed the recurrence of a few micropolyps in the rectal stump. No other member of the
family showed features of polyposis. Lower endoscopies were normal in the two offsprings of the
proband.
The most interesting aspect of the family was the molecular characterization, the proband being
heterozygous and the proband’s brother homozygous for the same MutYH mutation.
Molecular characteration
Mutation detected
Gene: MutYH
Exon: 14
Type of alteration: 1395 del GGA/wt (proband)
1395 del GGA/1395 del GGA (II-3)
Functional change: Removal of a glutamic acid within a highly conserved region of the protein.
45
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 5
2
1
I
a 85
K uterus 81
1
2
II
AFAP 50
AFAP 50
1
2
III
a 36
a 35
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
II-1
AFAP
50
Sebaceous lesion
of the skin
Right
Hemicolectomy
MutYH +
II-2
AFAP
50
Gastric Polyps
Thyroid Nodule
Colectomy and
IRA
MutYH +
46
History of the proband and the family.
In 2000, the proband (II-2) complained rectal bleeding and abdominal pain, at the age of 50 years.
Colonoscopy disclosed the presence of numerous polyps in the various large bowel tracts. In the
same year, the patient underwent colectomy and ileorectal anastomosis. At anatomical examination
a total of 24 polyps (tubular and tubulovillous adenomas with low-medium grade dysplasia) were
detected. At subsequent follow-up, small polyps (hyperplastic) of the rectal stump were removed.
The first upper endoscopy showed the presence of glandular polyps of the stomach (2004). During
follow-up a large adenoma (3 cm) of the gastric fundus was detected and removed (2008) through
endoscopy (tubulovillous adenoma with medium grade dysplasia). At both examinations the
duodenum was normal. A small thyroid nodule (6 mm) was observed in 2003 (not biopsed).
The brother of the proband (II-1) underwent colonoscopy in 1996 owing to aspecific abdominal
symptoms. Some 25-30 polyps were detected, predominantly localized in the proximal colon, and
the patient was operated on of right hemicolectomy (1996). Small polyps (hyperplastic and
adenomatous) were detected during surveillance of the remaining colon (2000, 2003, 2005). Small
sebaceous lesions were removed from the face (2005). The proband’s mother died of cancer of the
uterus (not otherwise specified).
Molecular characteration
Mutation detected
Gene: MutYH Exon: 7 Type of alteration: Y165C/G382D (compound heterozygosis)
Functional change: Reduced activity of the MutYH protein (Y165C) ;
Amino Acid change (G382D).
47
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 6
1
2
I
a 85
1
2
a 96
4
3
5
II
a 61
AFAP +
K cecum 60
a 71
2
1
4
a 67
a 56
5
6
3
III
a 37
0
a 41
a 44
a 42
a 36
a 34
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-3
AFAP +
K Cecum
60
None
Subtotal
Colectomy
and IRA
Negative (MutYH)
In progress (APC)
48
History of the proband and the family.
The proband (II-3) underwent colonoscopy in 2000, at the age of 60 years, because of abdominal
discomfort and anaemia; the endoscopist described the presence of about 50 polyps, both sessile
and pedunculated, ranging between 0.5 and 1.5 cm in diameter, distributed along the various tracts
of the large bowel. In the splenic flexure a vegetating mass of 6.0 cm of diameter suspected of
malignancy was noted. After a few months, the patient was operated on of subtotal colectomy and
IRA (December 2000). At anatomical examination, 30 lesions were analyzed; the majority of them
were adenomatous polyps with various degrees of dysplasia. In the splenic flexure, a TNM I
(T2N0M0, Dukes A) adenocarcinoma was diagnosed. At least two successive endoscopic controls
resulted negative. Similarly, the search for extracolonic changes (osteomas, retinal spots, gastric and
duodenal polyps) was negative. From 2005 we lost the patient from follow-up. No other member of
the family showed features of polyposis, although sporadic adenomas were removed during
colonoscopy in patients II-2 and II-5.
Molecular characteration
Search for mutation in the MutYH gene: negative.
Study of APC gene in process.
49
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 7
1
2
I
a 91
K pancreas 83
1
2
II
K uterus
45
AFAP + K duodenum
59
1
2
a 46
a 39
III
a 30
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-2
AFAP
59
Duodenal Cancer
age 59
1st operation
Subtotal Colectomy
and IRA
2nd operation
Duodenocefalopancreasectomy
Mutations
(APC/MutYH)
Negative
50
History of the proband and the family.
In 2005, at the age of 59 years, the proband of this family (II-2) complained persistent abdominal
pain, which was followed by jaundice. The patient was hospitalised and underwent a series of
investigations. An upper abdomen ultrasound study showed the presence of multiple stones in the
gallbladder and bile duct; moreover, gastroscopy revealed a large (5x7 cm) polyp of the duodenum,
extended to the entire circumference around the papilla of Vater. Another polyp (2 cm) protruded
from the papilla. Colonoscopy showed the presence of nearly 20 polyps in the various segments of
the large bowel, ranging between 1 and 3 cm in diameter. Bile duct stones were treated successfully
by endoscopy; the patient was subsequently operated on (2005) of subtotal colectomy and ileorectal
anastomosis. At anatomical description “numerous” (between 30 and 50 according to the wife)
polyps were observed of various dimensions (tubular adenomas with villous component and
moderate to severe dysplasia but without evidence of infiltrating malignancy). After a few months
(November 2005), the patient was operated on of duodeno-cefalo-pancreasectomy (the polyps could
not be removed endoscopically). Histology could not be obtained, but malignant changers were
likely. In fact, after 3 years the patient developed hepatic metastases and died within a few months
despite chemotherapy. No other extracolonic manifestations could be detected. In the family, the
sister of the proband was operated on for a carcinoma for the uterus (not otherwise specified) at the
age of 45 years; she is at present in good health at age 68. The father of the proband died of
pancreatic cancer at age 83. As far as we know, no other member of the family showed colorectal
polyposis.
Molecular characteration
No MutYH or APC mutations were detected.
51
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 8
1
2
I
1
II
2
3
4-6
7
3
1
AFAP+
K colon 72
AFAP?
K(?)
1
2-11
12-14
3
10
III
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-1
AFAP + K Colon
72
_
Subtotal
Colectomy
and IRA
Mutations
(APC/MutYH)
Not Tested
52
History of the proband and the family.
The information obtained from this family is fragmentary and insufficient for several reasons,
including poor collaboration. The proband (II-1) was affected from the birth by a severe mental
disease (not otherwise specified) and spent her life in a hospice. In 1987, at the age of 72, she was
hospitalized because of severe abdominal pain and rectal bleeding. At lower endoscopy, numerous
small sessile polyps were detected in the sigmoid, descending, transverse and ascending colon.
After one month, the patient was operated on of subtotal colectomy and ileorectal anastomosis.
At anatomical examination, nearly 50 sessile and peduncolated polyps were observed, ranging from
few mm to 1.5 cm. At histology, most of the lesions were tubular or villous adenomas with various
degrees of dysplasia; the largest polyps (sigmoid) showed features of infiltrative neoplasm (Dukes
A-TNM1 adenocarcinoma). The patient underwent endoscopic controls for the successive four
years, with removal of several newly developed adenomas. Rather unexpectedly, the patient died of
local recurrence in 1998 at the age of 83 years.
It was referred by the family doctor that a brother of the proband (II-2) was affected by polyposis,
but the finding has never been documented, and we have not been able to contact the patient or his
family. Another sibling presumably died of cancer but, again, confirmation was not obtained. Since
patients II-1 and II-2 had no offsprings, the disease presumably faded with them.
Molecular characteration
No molecular analyzes could be carried out in this family.
53
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 9
1
2
I
a 69
a 60
1
2
II
AFAP 18
a 18
III
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-1
AFAP
18
- Osteomas
- Gastric polyps
- Duodenal polyps
_
Mutations
(APC/MutYH)
APC +
54
History of the proband and the family.
The onset of the disease in this family was rather anomalous. In 2006, at the age of 18 years, the
proband (II-1) complained a certain difficulty in mastication, which was attributed to mandibular
osteomas (documented through a radiogram). In the suspicion of polyposis/Gardener syndrome, the
patient underwent lower endoscopy, that showed the presence of around 30 polyps of 3 to 5 mm in
diameter in the ascending colon, sigmoid and rectum. Histological examination of 10 removed
polyps revealed features of tubular adenoma with low-grade dysplasia. The patient started treatment
with Celecoxib (200 mg/day); subsequent endoscopies (2007, 2008) confirmed the presence of
polyps, which appeared unchanged in size, number and histological features. A gastroduodenoscopy
(2006) showed the stomach carpeted by small lesions (glandular polyps, 2-4 mm in diameter) and a
normal duodenum. At a subsequent gastroscopy, the stomach appeared unmodified, while numerous
polyps of 2-3 mm in size appeared in the duodenum (tubular adenomas, low-grade dysplasia).
Both the proband’s parents underwent colonoscopy, which was unremarkable.
Molecular characteration
Mutation detected
Gene: APC
Exon: 15 Type of alteration: 4612 del GA
Functional change: formation of a stop codon (truncated protein)
55
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 10
1
2
I
a 82
a 81
2
1
3
II
AFAP+ K rectum 40
a 39
a 59
1
2
3
III
a 21
a 15
a5
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-2
AFAP +
Cancer of
the Rectum
40
_
Anterior Resection
of the Rectum
Negative (MutYH)
In progress (APC)
56
History of the proband and the family.
The proband (II-2) was operated on for rectal carcinoma (Dukes C) in 2001, at the age of 40 years,
owing to rectal bleeding. At anatomical examination, “numerous” (4) polyps were seen around the
tumor mass, ranging from 0.6 to 1.0 cm in diameter (tubular adenomas, with low medium-grade
dysplasia). In the subsequent years the patient underwent several colonoscopies, which revealed the
presence of one or more small adenomas. In one of these controls (2005) more than 20 small
adenomas in the sigmoid and descending colon were observed and biopsed. The patient is still
under endoscopic control, with the constant removal of the lesions larger than 10 mm and the
careful observation of the smaller polyps.
In the family, only subject II-1 (proband’s brother) underwent colonoscopy, which showed the
presence of a few small polyps (removed). Apparently, this is an unusual family in which rectal
carcinoma developed some years before the appearance of attenuated polyposis
Molecular characteration
Absence of Microsatellite Instability (BAT25, BAT26, CAT25)
Search for constitutional mutations of MutYH gene: negative.
57
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 11
1
2
I
K colon
68
1
2
a > 70
3-5
II
3
3
K colon
63
K lung
78
AFAP 62
7
3
III
9
3
6-8
3
a 32
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-9
AFAP
62
_
_
a 28
Mutations
(APC/MutYH)
Negative (MutYH)
In progress (APC)
58
History of the proband and the family.
At the age of 48 years, the proband underwent lower endoscopy because of rectal bleeding; a small
(5 mm) polyp of the sigmoid was found. Subsequent endoscopies (1996, 2001) were negative but,
in 2007, twenty micropolyps were observed and removed. Anatomical examination revealed tubular
or tubulovillous adenomas with various degrees of dysplasia. Six more adenomatous lesions were
removed in 2008, at age 63. No surgical operation was taken into consideration, and the patient
continued with endoscopic follow-up.
Two components of the family (II-1, proband’s sister and I-1 proband’s father) died of colorectal
cancer (document in the sister, by history in the father), but apparently without features of
polyposis. Another sibling of the proband (II-2) died of lung cancer at age 78.
The case is of interest, mainly because there is evidence of polyp appearance at the age of 62,
whereas previous endoscopies did not show features of polyposis.
Molecular characteration
Search of MutYH mutations: negative.
APC gene analysis: in process.
59
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 12
1
2
I
a 75
K adrenal gland
65
2
1
3
II
1
a 50
a 54
AFAP 41
2
3
4
5
6
a 23
a 21
a 15
a 25
a 22
III
a 28
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
II-1
AFAP
41
_
Surgery
_
Mutations
(APC/MutYH)
Negative
I
60
History of the proband and the family.
Because of abdominal discomfort, the proband (II-1) underwent colonoscopy in 1996, at the age 41
years. This revealed the presence of numerous polyps in the transverse, descending and sigmoid
colon. A total of 42 lesions were removed and analyzed (2-5 mm in diameter, tubular adenomas
with low-grade dysplasia; in only one of the adenomas an area of severe dysplasia was observed).
Other small adenomas were removed during the numerous endoscopies carried out between 1997
and 2007 (the colonoscopy has never been “negative”). The search for extracolonic manifestations
(retinal spots, osteomas, dental abnormalities, gastric and duodenal polyps) was negative. A thyroid
adenoma (2.1 cm in diameter) was diagnosed in 1997. At the last control (February 2009) a total of
10 lesions were removed from the transverse, descending, sigmoid and rectum, 3 to 5 mm in
diameter (tubular adenomas with low grade dysplasia).
No other member of the family showed features of polyposis. The father of the proband, however,
underwent the removal of an adrenal gland tumor at the age of 65 years, and a few years later
polyps were removed from the bladder. In the older son of the proband (III-1), colonoscopy was
negative.
Molecular characteration
No APC or MutYH mutations were detected.
61
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 13
1
2
I
K colon 70
1
a 86
2
3
4
II
AFAP+
K colon 47
1
2
AFAP+
K colon 47
a 58
3
4
5
AFAP 39
6
7
a 18
a 16
III
a 37
a 34
a 19
a 16
a 11
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II- 1
AFAP +
K Colon
47
_
_
Not tested
II- 3
AFAP +
K Colon
47
_
_
Not tested
III- 4
AFAP
K Colon
39
46
_
Left
Hemicolectomy
(age 46)
Negative
62
History of the proband and the family.
The proband (II-4) underwent lower endoscopy in 2000, at the age of 39 years, upon suggestion of
the family doctor (after the death of her brother). In the transverse, descending and rectosigmoid
colon a total of 30 polyps were observed, ranging from 3 mm to 2.0 cm in diameter, many of which
were removed (tubular adenomas with moderate dysplasia). The patient went on with irregular
endoscopic controls. Surgery was suggested, but the proband postponed the decision and chose to
be cured with alternative/complementary remedies (Achillea, Ginkgo, Hypericus and others). At the
last endoscopy, the suspicion of malignancy in one of the largest polyps was raised; the patient was
operated on of left hemicolectomy as her own choice (the surgeon had suggested colectomy and
ileorectal anastomosis), in 2007. The anatomical examination confirmed the presence of a TNM II
adenocarcinoma of the sigmoid. The search for extracolonic manifestation was negative (retinal
spots, gastric or duodenal polyps, osteomas).
Information on the family was scanty; two of the 3 siblings were affected by colorectal neoplasia
both at the age of 47 years, presumably over a background of polyposis, and both died shortly after
diagnosis. The proband’s father (I-1) died of colorectal cancer at age 70, but no further information
was available. It is tempting to speculate that a deleterious mutation transmitted vertically from the
father to three of the offsprings was present; however, no constitutional alteration has so far been
detected.
Molecular characteration
No mutations in the APC or MutYH genes were detected.
63
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 14
1
2
I
a 53
a 85
1
2
II
a 61
AFAP 54
2
3
a 28
a 23
1
III
a 30
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-2
AFAP
54
_
_
Mutations
(APC/MutYH)
In progress
64
History of the proband and the family.
The proband executed a fecal occult blood test within a screening program of the Region EmiliaRomagna. Since the search for occult blood was positive, he underwent colonoscopy; this revealed
the presence of nearly 30 polyps, from 0.5 to 3.0 cm, in the rectal ampulla (the largest), in the
sigmoid and transverse colon. All the lesions were removed during two successive endoscopies
(2006, at the age of 54 years). At histological examination, features of tubular or tubulo-villous
adenomas were seen in all removed lesions. Three micropolyps were taken off in a subsequent
endoscopy, in 2007. An upper gastrointestinal endoscopy (2008) showed mild esophagitis. The last
colonoscopy (2008) was unremarkable; in the same year a blood sample was taken for genetic tests.
No other member of the family showed features of polyposis.
Molecular characteration
Analysis of APC and MutYH genes in progress.
65
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 15
1
I
2
K lung 81
K prostate 81
a 81
1
II
2
AFAP + K colon
52
a 61
1
III
a 26
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-1
AFAP + K Colon
52
- Mitral insufficiency
- Hypertension
- Hyperlipidemia
Colectomy
and IAA
(J pouch)
Negative
66
History of the proband and the family.
In June 2006, at the age of 52 years, the proband (II-1) complained abdominal pain and constipation.
A subsequent colonoscopy showed the presence of a rectal malignancy surrounded by numerous
polyps in the rectum, sigmoid and descending colon. The patient was operated on of colectomy and
ileoanal anastomosis. At anatomical examination a T3N2 (Dukes C) moderately differentiated
adenocarcinoma was diagnosed; nine of the polyps (which were not counted) were analyzed and all
showed features of adenomatous changes with various degrees of dysplasia. One month before
colonoscopy, a chest radiogram had revealed the presence of an undefined opacity in the inferior
lobe of the left lung. A subsequent CAT scan, followed by PET, confirmed the presence of a
possible lung malignancy. Gastroduodenoscopy revealed chronic gastritis with intestinal metaplasia
(HP-). In 2007 the patient underwent lobar resection of the left lung for removing the suspected
neoplasm; the histological diagnosis was adenocarcinoma, interpreted as metastasis of colorectal
cancer. The patient was treated with adjuvant chemotherapy (6 cycles). After one year (2008) the
patient was again operated on for removal of a newly developed nodule at the apex of right lung.
The patient is at present under chemotherapy (5-Fluorouracyl, Oxalyplatin and Folic Acid). A
recent clinical evaluation revealed insufficiency of the mitral valve, hypertensive cardiomiopathy,
and hyperlipidemia.
Among relatives, the proband’s father died of synchronous carcinoma of the lung and prostate, at
the age of 82 years. No other member of the family showed features of polyposis.
Molecular characteration
Genes tests negative for APC and MutYH mutations.
67
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 16
1
2
I
a 42
K lung 78
1
2
3
II
AFAP +
K colon 56
a3
1
AFAP +
K colon 54
2
3
a 53
a 47
III
a 59
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
II-2
AFAP +
K Colon
56
_
Subtotal
Colectomy (?)
Not tested
II-3
AFAP +
K Colon
54
_
Abdominoperineal
Resection
Not tested
68
History of the proband and the family.
Information about this family is scanty and fragmentary. Patient II-2 (proband’s sister) was operated
on for synchronous colorectal tumors in 1973, at the age of 56 years. According to the sister,
“numerous” polyps were also present, but no documentation was available. The patient died in 1990
for unknown reasons. The proband (II-3) was operated on of abdominoperineal (Miles) resection in
1987 (at the age 54 years) because of a rectal neoplasm; no polyps were referred at that time. In a
subsequent endoscopic control (through the stoma), at least 20 sessile polyps were observed in the
various tracts of the large bowel, ranging between 0.5 and 2.0 cm in diameter (tubular and tubulovillous adenomas with moderate-severe dysplasia). An upper endoscopy, carried out in the same
year, was normal. After 3 years (1990) the patient was operated on again for a metachronous tumor
of the large bowel. The patient was in relative good health in 1999; since then we lost any contact
with the family.
Molecular characteration
No molecular test was carried out.
69
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 17
1
2
I
a 74
a 75
2
1
3
II
K uterus 58
1
2
3
a 59
a 51
a 57
AFAP +
K colon 50
a 71
4
5
a 48
a 43
6
7
a 35
a 32
III
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-2
AFAP + K Colon
50
Acute Pancreatitis
Proctocolectomy
and IAA
0
Mutations
(APC/MutYH)
Not tested
70
History of the proband and the family.
As early as 1987, the proband (II-3) began to complain abdominal discomfort and pain. In the
following years he noted frequent diarrhea with rectal bleeding and weight loss. A barium enema
(1990) showed features of diffuse polyposis of the large bowel and the suspicion of an infiltrative
lesion of the sigmoid. The patient was operated on of total proctocolectomy and IAA (1990). At
anatomical examination, a 4 cm large TNM II (Dukes B) adenocarcinoma of the sigmoid was
diagnosed, together with diffuse polyposis of all colonic segments. A total of 81 lesions were
counted, ranging from a few mm up to 3.0 cm in diameter (tubular or tubulovillous adenomas with
various degrees of dysplasia). During follow-up, micropolyps of the pouch and of the terminal
ileum were observed and removed (1992, 1993). No extracolonic lesions could be documented.
The patient died in 1997 (age 57) of acute pancreatitis.
No other members of the family showed features of polyposis; in particular, all members of the
third generation (including the proband’s offsprings) underwent colonoscopy, which resulted
negative. It is likely therefore that the deleterious tract extinguished with the proband.
Molecular characteration
No test has been carried out.
71
I
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 18
2
1
I
K colon 48
1
K stomach 93
2
3
4
II
a 77
1
a 75
a 65
2
4
5
a 63
6
7
8
3
III
a 48
a 39
a 46
a2
a 39
AFAP 31
2
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
III-1
AFAP
31
_
_
Mutations
(APC/MutYH)
Not tested
72
History of the proband and the family.
In 2005, at the age of 31, the proband (III-8) underwent colonoscopy in absence of symptoms, but
worried for polyp occurrence in the father (II-3) and one of the uncles (II-2). The examination
revealed the (curious) presence of 10 polyps of large dimensions (2-3 cm in diameter) clustered in a
small area of the sigmoid, at 25-30 cm from the anal verge. The remaining tracts of the bowel were
normal. All polyps were removed in two successive endoscopic examinations (tubular and
tubulovillous adenomas with moderate to severe dysplasia). Since then the proband has been under
close surveillance, although she refused genetic testing. No surgery has been carried out. The last
endoscopic control (2007) was negative.
The family history is rather interesting. The paternal grandfather died of colorectal cancer at the age
of 48 years (I-1); we do not know whether adenomas were presence around the malignancy. Three
to 5 polyps were also removed endoscopically in the proband’s father (II-4), at the age of 52, and in
the uncle (II-2), at age 67. In both cases, histology showed the coexistence of adenomatous and
hyperplastic features.
Molecular characteration
No genetic test has been carried out.
73
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 19
1
2
I
AFAP + K colon
63
K colon 66
1
II
2
AFAP 35
3
AFAP 34
a 28
1
III
a 10
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
Mutations
(APC/MutYH)
I-2
AFAP +
K Colon
63
_
Colectomy
APC +
II-1
AFAP
35
_
_
APC +
II-2
AFAP
34
_
_
APC +
74
History of the proband and the family.
The information gathered from this family is limited. The proband’s mother (I-2) was operated on
of colectomy at age 63 because of a stage II (Dukes B) colorectal carcinoma over a background of
polyposis (2005). In the same year the proband (II-1) underwent the first colonoscopy, which
showed the presence of 20-30 polyps scattered in the various tracts of the large bowel, sessile, 4-6
mm in diameter. The removed lesions showed features of tubular adenomas with low-grade
dysplasia. Subsequent endoscopies (2006 to 2008) showed a gradually increasing number of polyps,
approximately of the same dimensions and histological aspect. Gastroduodenoscopy was
unremarkable (2006). Thus far the patient has not been operated on.
In 2006, attenuated polyposis has also been diagnosed in the proband’s sister, although further
details are lacking. Genetic tests have been carried out in the proband, the proband’s mother and
sister (II-2); the other sister (II-3) chose not to be tested.
Molecular characteration
Mutation detected
Gene: APC
Exon: 6
Molecular Alteration: 677-684 del 8 ins 4 (deletion of AGGACATA at position 677-684, and insertion
of TTTC)
Functional consequences: truncated protein.
75
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 20
1
2
I
a 60
a 60
1
2
II
AFAP 33
a 33
1
2
III
a 10
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-1
AFAP
33
Gastric polyps
Duodenal polyps
Proctocolectomy
and IAA
Mutations
(APC/MutYH)
APC +
76
History of the proband and the family.
Owing to persistent rectal bleeding, the proband (II-1) was investigated by lower endoscopy in
2000, at the age of 33 years. The endoscopist described “numerous” sessile polyps (less than 100) in
the entire colon, 20 of which localized in the rectum. The removed lesions showed features of
tubular and tubulovillous adenomas with moderate dysplasia. After five months, the patient was
operated on of proctocolectomy and IAA. The anatomical description is lacking, however, no signs
of malignancy were observed. During the hospitalization, an upper gastrointestinal endoscopy
revealed the presence of numerous sessile polyps in the gastric antrum and fundus (glandular
polyps), and a few sessile polyps of the duodenum (tubular adenomas with moderate dysplasia).
After the operation, the patients had loosy stools and frequent defecation for several months, but the
situation improved gradually over time.
No other component of the family showed features of polyposis nor was affected by neoplasms.
Molecular characteration
Mutation detected
Gene: APC
Exon: 15 Type of change: 3336 del 5
Functional consequences: formation of a truncated protein.
77
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 21
1
2
I
a 68
1
a 74
2
3
II
a 80
AFAP 75
a 81
2
3
1
III
a 45
a 58
a 56
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-3
AFAP
75
- Diabetes
- Hypertension
- Atrial fibrillation
- Chronic Obstructive
Lung Disease
Subtotal
Colectomy
and IRA
Mutations
(APC/MutYH)
In progress
78
History of the proband and the family.
Starting at the age of 60 years, the proband (II-3) had a series of relevant diseases, including insulin
dependent diabetes, atrial fibrillation (treated with warfarin, and digoxin), chronic obstructive lung
disease (he had been a heavy smoker for many years) and hypertension (treated with diuretics and
ACE-inhibitors). In June 2008 (at age 75), he noted the presence of blood in the stools; a lower
endoscopy showed the presence of polyps in the large bowel. For the persistence of rectal bleeding,
after a few months the patient underwent subtotal colectomy with ileorectal anastomosis. At
anatomical examination, a total of 11 lesions were noted, between 1.0 and 2.0 cm in diameter,
distributed both in the proximal and in the distal colon. At histology, the lesions were tubular or
tubulovillous adenomas with moderate to severe dysplasia. A gastroduodenoscopy was
unremarkable. Despite the numerous comorbidities, the patient recovered quite well.
No other member of the family reported a clinical history of neoplasms or polyposis.
Molecular characteration
Search of mutations for the APC and MutYH genes in progress.
79
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 22
1
2
I
K colon 73
a 50
1
2
II
AFAP 72
K kidney 64
2
3
1
III
a 50
a 55
a 50
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II-2
AFAP
72
- Arterial occlusion
- Chronic gastritis
Subtotal colectomy
and IRA
Mutations
(APC/MutYH)
Not tested
80
History of the proband and the family.
The proband, II-2, had a long history of abdominal symptoms (pain, flatulence, rectal bleeding)
attributed to diverticulosis. For a further worsening of the clinical status, the patient was operated
on of subtotal colectomy and ileorectal anastomosis. At anatomical examination, a total of 19
adenomatous lesions were observed scattered in the various segments of the large bowel (tubular or
tubulovillous adenomas with various degrees of dysplasia), together with a few hyperplastic polyps
(2006). The patient underwent a colonoscopic control in 2008, which resulted negative.
Esophagogastroduodenoscopy (2006) showed chronic gastritis but no polyps. The patients had
serious vascular problems, which led, few years before colectomy, to amputation of the left leg.
In the family there are not other cases of polyposis. The proband’s father, however, I-1, died at the
age of 73 years for on advanced colorectal malignancy. The proband’s brother died at age 64 for a
neoplasm of the kidney.
Molecular characteration
No molecular test has been carried out.
81
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 23
1
2
I
K lung 73
1
a 79
2
3
II
AFAP 51
a 54
1
2
3
K breast 41
4
5
III
a 29
a 20
Patient
Diagnosis
Age
II-2
AFAP
51
a 21
a 19
Extracolonic
Manifestations
Other relevant
Diseases
_
a 17
Surgery
_
Mutations
(APC/MutYH)
Negative (MutTH)
In progress (APC)
82
History of the proband and the family.
Following a suggestion of the family doctor, the proband (II-2) executed a fecal occult blood test,
that resulted positive. After a few months, he underwent colonoscopy (2004), which showed the
presence of approximately 20 polyps distributed in the left and transverse colon. Eight of the lesions
were removed for further analysis. At anatomical and histological examinations, the polyps ranged
between 2.0 and 5.0 cm in diameter, with features or tubular or tubulovillous adenomas with
various degrees of dysplasia; in the largest lesion a “intramucosal carcinoma” was described. At a
subsequent endoscopy the remaining polyps were removed. During endoscopic follow-up (from
2005 to 2008), small sessile adenomas recurred in various segments of the large bowel (removed
and examined).
No other case of polyposis was reported in the family. The proband’s father presumably died of
lung cancer (he was a heavy smoker). The proband’s sister was operated on for breast cancer at the
age of 41 years.
Molecular characteration
MutYH gene analysis: negative for mutations.
APC gene analysis: in progress.
83
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 24
1
2
I
a 64
1
KSU 84
2
II
AFAP 66
a 72
1
III
2
a 40
a 38
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
II-2
AFAP
66
Chronic Gastritis
HP +
Surgery
_
Mutations
(APC/MutYH)
In progress
84
History of the proband and the family.
The proband (II-2) underwent colonoscopy in 2006, at the age of 66 years, owing to a positive fecal
occult blood test. The investigation showed a total of 11 polyps (from 5-6 mm to 3.0 cm in
diameter) distributed in the various tracts of the large bowel. Parts of the polyps were removed, and
histological examination revealed features of tubular adenomas (with moderate dysplasia) in all of
the lesions. In a successive investigation, in the same year, the remaining lesions were removed and
analyzed (again adenomas with various degrees of dysplasia). Newly developed adenomatous
lesions were removed by lower endoscopy in 2006 and 2008. A gastroduodenoscopy (2006)
showed HP + chronic gastritis of the antrum and duodenitis.
No other member of the family reported polyposis. The proband’s mother died at the age of 84 for a
malignancy not otherwise specified.
Molecular characteration
Search for mutations of the APC and MutYH genes in progress.
85
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 25
1
2
3
I
K colon 35
a 84
a 72
1
2
II
a 63
AFAP 63
1
2
3
III
a 37
a 21
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
II-1
AFAP
63
Chronic Obstructive
Lung Disease
a 34
Surgery
_
Mutations
(APC/MutYH)
In progress
86
History of the proband and the family.
The proband, born in 1945, had a long history of severe chronic obstructive lung diseases, which
required periods of oxygen administration especially during the night, owing to frequent episodes of
nocturnal apnea; in addition, he was recently hospitalized for heart failure. He is taking several
drugs, including diuretics, aspirin and corticosteroids.
In 2008, because of a positive fecal occult blood test, he underwent colonoscopy, which showed the
presence of at least 50 sessile polyps, 5 to 10 mm in diameter, scattered throughout the large bowel,
but more dense in the proximal colon. Eight of the lesions were removed and examined (tubular
adenomas, tubulovillous adenomas with moderate to high-grade dysplasia). Surgery was taken into
consideration, but the decision was postponed owing to the severe lung disease. In the same year
(2008), more polyps were removed at a second endoscopy.
The only relevant, though not verified, information from the family was the early occurrence (35
years) of colorectal carcinoma in the proband’s paternal uncle. No other member of the family
showed features of polyposis.
Molecular characteration
Search for constitutional mutations in the APC and MutYH genes in progress.
87
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 26
1
2
I
K colon 65
1
a 81
2
3
II
AFAP 50
a 46
a 52
1
2
3
4
III
a 23
a 19
a 6
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
II-1
AFAP
50
- Chronic Lung Disease
- Obesity
- Depression
- Chronic arterial
occlusion
- Chronic Gastritis
and Duodenitis (HP+)
- Hyperplastic duodenal
polyps.
a 22
Surgery
_
Mutations
(APC/MutYH)
In progress
88
History of the proband and the family.
The proband (II-1, born in 1957) has a long history of chronic obstructive lung disease, arterial
occlusion of the legs (with claudicatio intermittens), obesity and depression, and is treated with
several drugs (including antidepressant, aspirin and corticosteroids). In 2007, owing to a positive
fecal occult blood test he underwent colonoscopy. This revealed the presence of nearly 30 polyps
regularly distributed in the various tracts of the large bowel, ranging between 3-4 mm to 4.0 cm in
diameter, both sessile and peduncolated. Eight lesions were removed and examined, and all showed
features of tubular adenoma with mild to moderate dysplasia. At subsequent endoscopies (2007 and
2008) several other lesions were removed, showing histological characteristics of adenomas or
hyperplastic polyps (the smaller). At the last endoscopy (February 2009), 2 small polyps were
detected (and removed) in the ascending colon (hyperplastic polyps of 0.6 and 0.8 cm in diameter).
A gastroduodenoscopy was carried out in January 2009; this showed severe gastritis and duodenitis
(Helicobacter Pylory +) and a small (0.5 cm) hyperplastic polyp of the duodenum.
In this family, no other subject showed features of polyposis; the proband’s father, however, died of
colorectal cancer at the age of 65 years, but further information is lacking.
Molecular characteration
Search for constitutional mutations of the APC and MutYH genes in progress.
89
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 27
1
2
I
a 72
1
2
a 91
3
4
5
II
a 74
a 71
K bladder 60
K colon 66
AFAP 67
7
1-2
III
2
3-4
a 60
8
5-6
2
2
a 37
a 35
Patient
Diagnosis
Age
Extracolonic
Manifestations
Other relevant
Diseases
Surgery
II- 4
K Colon
AFAP
66
67
Obesity
Hypertension
Right
Hemicolectomy
Mutations
(APC/MutYH)
In progress
90
History of the proband and the family.
The proband (II-4, born in 1940) is an obese individual (127 Kg, 177 cm) affected by hypertension
and in treatment with several drugs (aspirin, diuretics, ACE-inhibitors, and diet). After a positive
fecal occult blood test, he underwent colonoscopy (2006), which showed a vegetating lesion of the
cecum. The patient was operated on of right hemicolectomy; at anatomical examination, a T2N0M0
(Dukes A) adenocarcinoma was diagnosed. Together with the malignancy, a single adenoma was
noted in the resected specimen. After one year, the patient underwent a control colonoscopy (2007),
which showed the presence of nearly 80 small polyps - 3 to 6 mm in diameter - evenly distributed
throughout the remaining colon and rectum. Twenty of the lesions were removed and analyzed, and
all showed features of adenomatous polyps with mild dysplasia. The situation was virtually
unchanged at subsequent controls in September 2008 and December 2009. The patient was
suggested to undergo surgical removal of the remaining colon.
No other member of the family reported polyposis. The proband’s brother was operated on for a
bladder malignancy at the age of 60 years.
The interesting aspect of this case is the development of nearly 80 adenomas (2007) after the
removal of the right colon one year before (2006), when the patient was already 67 years old.
Molecular characteration
Search for constitutional mutations of the APC and MutYH genes in progress.
91
ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) N. 28
2
1
I
a 62
1
a 71
2
3
II
1
2
a 40
a 43
AFAP 35
3
5
6
4
III
a 25
Patient
Diagnosis
a 18
a 16
a3
Age
g
II-1
44
AFAP
Extracolonic
Manifestations
1 Other relevant
Diseases
_
a9
a4
Surgery
_
Mutations
(APC/MutYH)
In progress
92
History of the proband and the family.
The proband (II-1) had a history of gynaecological troubles. At the age of 28 years (1988), she had
the right ovary removed for a dermoid cyst; twelve years later (2000), owing to frequent vaginal
bleeding and consequent anemia, she underwent extended hysterectomy.
In 2003 she noticed the presence of blood in the stools, a symptom which remained overlooked for
more than one year. In 2004 she executed the first lower endoscopy, which revealed the presence of
“numerous” polyps (adenomas) of the large bowel. In the subsequent years she underwent several
endoscopic investigations, with removal of the newly developed lesions. Despite a close control, in
2007 a total of 18 polyps were counted, 3 in the rectosigmoid, 5 in the descending and 10 in the
transverse colon. All lesions showed features of tubular adenomas with low-grade dysplasia. At the
last endoscopic control (2009), 14 lesions were detected (again adenomas with low-grade
dysplasia), one of which was a flat adenoma of 20 mm in diameter.
No other first-degree relative of the proband reported history of cancer or intestinal polyps;
however, a paternal uncle died at the age of 65 years for a colorectal malignancy (not reported in
the family tree).
Molecular characteration
Search for mutations of the APC and MutYH genes in progress.
93
SUMMARY TABLES OF THE MAIN RESULTS OBSERVED IN THE 27 FAMILIES
WITH AFAP
Table 1 summarizes the main clinical findings observed in 36 patients (28 families) with
documented attenuated polyposis. Most of the families showed only 1 affected individual (22 out of
28, 78.6%), and in only 6 families there were 2 or more cases of AFAP. Mean age at diagnosis of
AFAP was 51.8 ± 15 (mean ± SD), ranging between 18 and 75 years. Surgery was carried out in
about half of the patients (18 out of 36, 50.0%); it follows that the remaining 18 individuals were
managed through endoscopy. Extracolonic manifestations were identified in 5 individuals (13.9%)
although in many cases they were not searched for. The number of synchronous polyps, usually
detected at the first endoscopic investigation, ranged between 10 and 81, with a mean of 34.9 ± 21;
in only two cases (n.15 and n.20) the investigators failed to establish the number of polyps, but
preferred to say “numerous” or less than 100. In 14 out of 36 patients (39%), one or more
carcinomas of the large bowel had developed at the time of diagnosis. Finally, of the 15 families in
which complete genetic test could be carried out, 5 resulted positive (33.3%, 2 MutYH and 3 APC
mutations).
Constitutional mutations identified in 5 unrelated families are shown in details in Table 2. In
family 4, the same mutation (1395delGGA of MutYH gene) was present in heterozygosis in the
proband and in homozygosis in the proband’s brother.
Table 3 illustrates the main surgical operations carried out in the 18 patients who underwent
surgery. The data are subdivided in two study-periods (1980-1999 and 2000-2008) and by 3
different approaches. Even in the most recent times, subtotal colectomy with ileorectal anastomosis
represents the most frequent type of surgery.
The main clinical features of the five families which resulted positive for constitutional
mutations versus the 10 families that resulted negative are illustrated in Table 4. The data are not
sufficient to allow firm conclusions, however, mean age at diagnosis tends to be earlier in Mut +
than in Mut – individuals; moreover, extracolonic manifestations were more frequent (in Mut +
patients). Rather surprisingly, more synchronous colorectal malignancies were observed among
Mut– families.
Table 5 compares some of the basic clinical data between AFAP and FAP families, each
subdivided in symptomatic and asymptomatic patients. Data of FAP families have already been
published (1, 2, 3). It is of interest to note that FAP was diagnosed on average about 20 years earlier
than AFAP, unregarding to the presence of symptoms. Moreover, in the case of AFAP there was a
relatively small interval in age at diagnosis between symptomatic and asymptomatic patients. As a
consequence of these findings, early diagnosis and prevention of cancer are considerably more
difficult in AFAP than in FAP, as this is further demonstrated by the higher fraction of malignant
neoplasms detected among asymptomatic patients (21.5% versus 9.4% in FAP).
Finally, Table 6 compares constitutional mutations of the two main genes in patients with
AFAP and in those with classical Adenomatosis Coli (1, 2, 3). As expected, and reported in the
literature (4, 5), the percent of positivity was much lower in AFAP (33.3% vs 82.2%, though in
many families molecular analysis is still in progress). While the main role played by the APC gene
in FAP and quite clear, the relative contribution of APC and MutYH to the AFAP phenotype should
be clarified by further investigations.
94
References
1. Ponz de Leon M, Benatti P, Percesepe A, Cacciatore A, Sassatelli R, Bertoni G, Sabadini G,
Varesco L, Gismondi V, Mareni C, Montera M, Di Gregorio C, Landi P, Roncucci L.
Clinical features and genotype-phenotype correlations in 41 Italian families with
adenomatosis coli. Ital J Gastroenterol Hepatol. 1999 Dec;31(9):850-60.
2. Ponz de Leon M, Varesco L, Benatti P, Sassatelli R, Izzo P, Scarano MI, Rossi GB, Di
Gregorio C, Gismondi V, Percesepe A, de Rosa M, Roncucci L. Phenotype-genotype
correlations in an extended family with adenomatosis coli and an unusual APC gene
mutation. Dis Colon Rectum. 2001 Nov;44(11):1597-604.
3. Ponz de Leon M, Pezzi A, Roncucci L, Benatti P, Rossi G, Di Gregorio C, Sassatelli R,
Pedroni M, Maffei S, Borsi E, Domati F, Nozzi D, Bursi E, Mora E, De Gaetani C. Poliposi
Familiare del Colon-Retto (Adenomatosis coli). L’esperienza di un Gruppo di studio sui
Tumori Colorettali dell’Università di Modena e Reggio Emilia e dell’Azienda Policlinico.
Università di Modena e Reggio Emilia, pag. 1-175, 2008.
4. Knudsen AL, Bisgaard ML, Bülow S. Attenuated familial adenomatous polyposis (AFAP).
A review of the literature. Fam Cancer. 2003;2(1):43-55.
5. Lipton L, Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer.
2006;5(3):221-6.
95
Table 1. Main clinical features in the whole study Group (28 families)
Family
Affected
patients
(n.)
Age at
diagnosis
Sex
Surgery
Extracolonic
manifestations
N. of
colorectal
polyps
K
colon
Mutation
N. 1
N. 2
N. 3
N. 4
N. 5
N. 6
N. 7
N. 8
N. 9
N. 10
N. 11
N. 12
N. 13
1
1
1
2
2
1
1
2
1
1
1
1
3
65
35
49
45
50
60
59
72
18
40
62
41
44.3
+
+
+
+
+
+
+
+
+ (1)
+
+
+
-
78
30
22
50 / 11
24 / 30
50
20
50
30
20
20
42
30
+
+
+
+
+
+
+ (3)
Not tested
Neg
Neg
+ (MYH)
+ (MYH)
Neg
Neg
Not tested
+ (APC)
Neg
Neg
Neg
Neg
N. 14
1
54
M
F
M
M/F
M/F
F
M
M/F
F
F
M
F
F
(2)/M
M
-
-
30
-
N. 15
N. 16
N. 17
N. 18
N. 19
N. 20
N. 21
1
2
1
1
3
1
1
52
55
50
31
44.5
33
75
M
F (2)
M
F
F (3)
M
M
+
+ (2)
+
+ (1)
+
+
+
-
Numerous
20
81
10
25
< 100
11
+
+
+
+ (1)
-
N. 22
N. 23
N. 24
1
1
1
72
51
66
M
M
M
+
-
-
19
20
11
-
N. 25
1
63
M
-
-
50
-
N. 26
1
50
M
-
+
30
-
N. 27
1
67
M
+
-
80
+
N. 28
1
44
F
-
18
-
51.8 ± 15
(mean ±
SD)
Range: 1875
M 19
F 17
+ = 18
─ = 18
34.9 ± 21
(mean ±
SD)
+ = 14
─ = 22
Patients =
36
Families
= 28
+=5
In
progress
Neg
Not tested
Not tested
Not tested
+ (APC)
+ (APC)
In
progress
Not tested
Neg
In
progress
In
progress
In
progress
In
progress
In
progress
Positive =
5
Negative
= 10
Not tested
=6
In
progress
=7
96
Table 2. Constitutional mutations identified in 5 families with AFAP
Family
Gene
Exon
Type of alteration
Functional Consequence
Gene carriers
AFAP 4
MutYH
14
1395delGGA
Truncated protein
2
AFAP 5
MutYH
7
Y165C/G382D
Truncated protein
2
AFAP 9
APC
15
4612delGA
Truncated protein
1
AFAP 19
APC
6
677-684del8ins4
Truncated protein
3
AFAP 20
APC
15
3336del5
Truncated protein
1
Table 3. Type of colorectal surgery carried out in AFAP patients (n. 18).
Period
Subtotal
colectomy and
IRA
Proctocolectomy
and IAA
Segmental
resection or
Hemicolectomy
Total
1980 – 1999
4
1
1
6
2000 – 2008
6
3
3
12
97
Table 4. Clinical features in Mut + (n. 5, APC or MutYH) versus Mut – (n. 10, in which the test
resulted negative) families.
Mean age at
diagnosis
Surgery
Mean number
of adenomas
Colorectal
Cancer at
diagnosis
Extracolonic
Manifestations
Mut +
(n. 5)
38.5 ± 13.0
4/5 (80%)
28.3 ± 12
2/5 (40%)
3/5 (60%)
Mut –
(n. 10)
49.3 ± 9.0
6/10 (60%)
28.2 ± 11
7/10 (70%)
1/10 (10%)
Table 5. Age at diagnosis, number of adenomas and cancer occurrence in symptomatic and
asymptomatic AFAP patients, and in patients with FAP. *
Mean age at diagnosis
Average number of
adenomas
Patients with
colorectal cancer at
diagnosis
Symptomatic AFAP
patients (n. 16)
54.9 ± 12.1
33.8 ± 22.0
8/16 (50.0%)
Asymptomatic AFAP
patients (n. 14)
47.9 ± 15.2
32.2 ± 19.1
3/14 (21.5%)
Symptomatic FAP
patients (n. 67)
35.5 ± 11.8
> 100
36/67 (53,7%)
Asymptomatic FAP
patients (m. 32)
23.3 ± 11.0
> 100
3/32 (9.4%)
* M.Ponz de Leon et al. “Poliposi Familiare del Colon-retto”, pag 1-175; Università degli Studi di
Modena e Reggio Emilia, ottobre 2008.
98
Table 6. APC and MutYH mutations detected in AFAP and FAP families. *
Families
(n.)
Positive for
mutations
Total
analyzed
%
positivity
APC
MutYH
AFAP
(28)
5
15
33.3%
3
2
FAP
(61)
37
45
82.2%
33
4
* M.Ponz de Leon et al. “Poliposi Familiare del Colon-retto”, pag 1-175; Università degli Studi di
Modena e Reggio Emilia, ottobre 2008.
99