Download Familial Adenomatous Polyposis From Bedside to Benchside

AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Review Article
Familial Adenomatous Polyposis
From Bedside to Benchside
MAUREEN J. O'SULLIVAN, MB, MD,1* TOMMIE V. MCCARTHY, PhD,2 AND CUIMIN T. DOYLE, MD, FRCPath1
Familial adenomatous polyposis (FAP) is a dominantly inherited cancer-predisposition syndrome with an incidence of
between 1:17,000 and 1:5,000. The condition has been causally
linked to mutation of the adenomatous polyposis coli (APC)
gene located at 5q21. Virtually all mutations in the APC gene
are truncating mutations, resulting in loss of function of the
APC protein. Spontaneous germline mutation of this gene
occurs frequently and accounts for the high incidence of FAP.
The gene is somatically mutated at an early point in the colorectal adenoma-carcinoma progression. Somatic mutations of
the APC gene are also frequently observed in a variety of other
human carcinomas.
Isolation of the APC gene has led to the recognition of genotype-phenotype correlations and, together with protein studies,
has helped to elucidate the structure and function of the APC
protein. This report aims to take the reader from a clinical appreciation to a molecular understanding of FAP. (Key words:
Familial adenomatous polyposis; Adenomatous polyposis coli
[APC] gene; Truncating mutations; APC protein; Germline mutation; Somatic mutation) Am J Clin Pathol 1998;109:521-526.
Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited cancer-predisposition syndrome that is causally linked to mutation of the adenomatous polyposis coli gene (APC) that has been
localized to 5q21. 1-11 The reported incidence ranges
from 1:17,000 to 1:5,000.12 Spontaneous germline
mutation is frequent, with resultant cases accounting
for up to 30% of patients. 1 3 Disease penetrance is
almost 100% at 40 years of age. 14
The disease is classically characterized by the
development, usually during the teenage years, of at
least 100 adenomatous polyps in the colorectum.
Because adenomatous polyps of the gastrointestinal
tract are premalignant, ultimate progression to carcinoma is inevitable in the absence of therapeutic intervention. 15 ' 16 The standard mode of intervention has
been surgical, in the form of prophylactic colectomy,
although medical therapy with sulindac, which has
been shown to induce polyp regression, 17 is undergoing trial by the English-based concerted action polyposis prevention group (J Burn, MD, oral communication, December 1994).
Adenomatous polyps may develop more proximally
in the gastrointestinal tract also, most notably in the
stomach and second part of the duodenum, where eradication and control of neoplastic progression are far more
challenging. Numerous extraintestinal lesions may
cosegregate with adenomatous polyposis. These include
desmoid tumors, exostoses of the long bones and endostoses (particularly of the mandible), which have been
loosely referred to as osteomas. Furthermore, congenital
hypertrophy of the retinal pigment epithelium (CHRPE;
a hyperpigmentation of the retina caused by increased
numbers of large pigment granules18,19), central nervous
system neoplasms, and epidermoid cysts also may be
featured in the disease. Traditionally, the association of
FAP, d e s m o i d s , and exostoses has been termed
Gardner's syndrome, 20-23 whereas the combination of
cerebral neoplasia and FAP is known as Turcot's syndrome. 24 These two syndromes have also been causally
linked to mutation of the APC gene. Less well established associations that have been reported include an
increased risk of development of pancreatic adenocarcinoma, 25 extrahepatic cholangiocarcinoma, hepatoblastoma, 26-28 papillary thyroid carcinoma,29'30 and several
of the multiple endocrine neoplasia syndromes. 31-33
From the ^Department of Pathology, Cork University Hospital and
the 2Molecular Biology Research Laboratory, Department of
Biochemistry, University College, Cork, Ireland.
Manuscript received May 28,1997; accepted June 27,1997.
Address reprint requests to Dr O'Sullivan: Lauren V. Ackerman
Laboratory of Surgical Pathology, Washington University Medical
Center, PO Box 8118, 660 S Euclid Ave, St Louis, MO 63110.
*Dr O'Sullivan is now affiliated with the Lauren V. Ackerman
Laboratory of Surgical Pathology, Washington University Medical
Center, St Louis, Missouri.
521
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AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Review Article
The APC gene was first identified in 1986, with the
observation of a constitutional interstitial deletion of a
segment of the long arm of chromosome 5 in a young
man with polyposis and numerous other congenital
anomalies. 1 The exact gene locus was then established
by positional cloning. 34-38 The APC gene has an open
reading frame of 8538 base pairs (bp)34 and comprises 15
coding exons, with exon 15 alone containing 6571 bp,
making it the largest known human exon. The gene
codes for a 2843 residue protein with a molecular weight
of 310 kD 3 4 , 3 6 and wide tissue expression, including
stomach, liver, esophagus, kidney, brain, and eye.
The APC gene was classified as a tumor suppressor
gene on the basis of the frequently observed loss of
heterozygosity at 5q21 in diverse tumors, including
those of the colorectum, and the finding that most
mutations (95%) reported in the APC gene are truncating and, therefore, presumably inactivating, mutations. 39 In addition, the Knudson "two-hit" model can
be applied to the APC gene in the development of colorectal carcinoma, both hereditary (FAP type) and
sporadic. Mutation of one allele is sufficient for the
development of adenomas, suggesting a dose-dependent effect by the gene product a n d / o r a dominant
negative effect by its mutated form.
To date, more than 300 different mutations of the
APC gene have been described. 40 These are distributed
throughout the whole gene, with a higher concentration in the 5' part of exon 15, where 60% of all reported
somatic mutations occur between codons 1000 and
1600 in the so-called mutation cluster region, which
comprises only 20% of the entire gene. 39 The majority
are frameshift mutations, resulting from deletions or
insertions of b e t w e e n 1 a n d 8 b p . A certain few
germline mutations are particularly prevalent, notably
the 5-bp deletions at codons 1061 and 1309, which represent 5% and 10% of the mutations in the German FAP
populations, respectively, 41 and together account for
approximately 20% of all mutations demonstrated in
the Italian population. 42 In the Irish population, these
m u t a t i o n s account for 6% a n d 11% of r e p o r t e d
germline APC gene mutations, respectively.43 Overall,
33% of all published APC gene mutations are located at
codons 1061, 1309, or 1465. 44 Larger deletions and
insertions have been reported, 3 9 ' 4 5 and isoforms of
messenger RNA lacking exon 7 or with alternative
splicing of exon 9 have also been described.36-46
The exact location of a mutation within the APC
gene seems to be significant for the disease phenotype.
Apart from variation in extraintestinal disease manifestations, the actual number of polyps is inconstant
also, with the disease being categorized as sparse when
fewer than 1,000 polyps are present and profuse when
more than 5,000 are present. 44 ' 47 Mutations proximal to
codon 1249 are associated with sparse polyposis,
mutations between codon 1250 and 1330 lead to a profuse phenotype, and mutations distal to codon 1465
again lead to sparse polyposis. Furthermore, the common mutation at codon 1309 has been linked to a more
aggressive disease course with earlier onset of gastrointestinal s y m p t o m s , 4 8 while m u t a t i o n at the
extreme 5' portion of the APC gene is associated with
"attenuated polyposis," characterized by the development of fewer polyps at a later age. 49 The presence or
absence of CHRPE is apparently attributable to the
location of a mutation within the APC gene. 50 CHRPE
is reportedly systematically present in patients in
whom the mutation lies downstream of exon 9, but is
absent in those in whom the mutation is located 5' of
exon 9 (Fig 1). No consistent relationship between the
exact mutation site and other extracolonic disease features has been demonstrated. 51,52
These findings, coupled with the observation of
somatic APC gene mutation as a key initial step in sporadic colorectal t u m o r i g e n e s i s , 5 3 h a v e p r o v o k e d
intense interest in the role of the APC protein. This is
a 2843 residue protein with cytoplasmic localization.
Wild-type APC protein complexes precipitate in the
insoluble cell membrane fraction.54
Early studies showed that the APC protein can be
subdivided into two major regions: the carboxy terminal 75% and the amino terminal 25%, the latter of
which contains proline-free blocks with heptad repeats
of hydrophobic residues. 34 This pattern is characteristic
APC Gene
Codon 1309—Aggressive course
Codon1
FIG 1. Familial adenomatous polyposis (FAP) genotype-phenotype
correlation: significance of the mutation site within the adenomatous polyposis coli (APC) gene. AAPC = attenuated form of familial adenomatous polyposis; CHRPE = congenital hypertrophy of
the retinal pigment epithelium.
AJCP • May 1998
O'SULLIVAN ET AL
523
Familial Adenomatous Polyposis
of oc-helical coiled coils and implies protein-protein
interactions. Studies of the binding properties of the
APC protein indicated that the amino terminus was
critical for homo-oligomerization. 5 5 The first 171
residues were found to be sufficient for complex formation; the first 45 residues proved essential (Fig 2,
A). Most APC gene mutations result in the production
of a protein that is truncated at some point beyond
r e s i d u e 171. T h u s , the p o t e n t i a l for c o n t i n u e d
oligomerization should generally be preserved in truncated proteins, permitting the formation of inactivating
complexes; this in essence could explain the dominant
negative effect by the mutant protein. Nondetection of
any protein smaller than 80 kd in transgenic mice suggests instability of these severely truncated proteins or
of their messenger RNA (R Fodde, MD, unpublished
data, 1994). Inactivating complexes cannot be formed
from such products because they lack the critical binding domain. Instead, in this situation, the total amount
of wild-type APC protein is reduced, and this reduction is believed to account for the attenuated form of
FAP observed when mutation occurs very proximally
within the APC gene.10-49
Further insight into the function of the APC gene
product came with the precipitation of 2 proteins that
were shown to associate with the region of the APC protein between residues 1014 and 1210. 56 Analysis
of these proteins characterized them as a- and
p-catenins.57 The catenins are a group of cytoplasmic proteins that were identified primarily because of their association with the cell adhesion molecule, E-cadherin.57 o
Catenin is structurally similar to vinculin, a known
junction-associated protein, and p-catenin shares substantial homology with armadillo, a Drosophila segment
polarity gene product involved in signal transduction.57
Protein fusion studies confirmed the association of the
catenins with the APC protein, which is demonstrably
independent of their interaction with E-cadherin.56'58 pCatenin interacts with the intracellular domain of E-cadherin, anchoring its cytoplasmic region to the adherens
junction,59 while its extracellular domain interacts homotypically with E-cadherin on adjacent cells. 5 9 The
adherens junction is critical for the establishment and
maintenance of epithelial layers, cell-cell adhesion, and
anchorage to the actin cytoskeleton. 59 ' 60 oc-Catenin is
believed to associate with E-cadherin and the APC protein indirectly, through its interaction with the amino-terminal portion of p-catenin. 56 ' 61 a-Catenin, which also
binds actin, is thus thought to link the adherens junction
and the APC protein to the actin cytoskeleton.
p-Catenin was recognized originally as a cadherinbinding protein; however, its Drosophila homolog
armadillo also has a role in signal transduction in the
wingless pathway, which determines segment polarity
and cell fate during embryogenesis. The roles of pcatenin in signal transduction and cell adhesion have
been shown to be distinct and separate. 58
The APC protein may regulate the role of p-catenin
in the Wnt-1 (the vertebrate oncoprotein counterpart
of wingless) signaling pathway. 62 ' 63 Initiation of the
mitotic signal via the Wnt-1 pathway causes posttranslational stabilization and cytoplasmic accumulation of P-catenin. The APC protein, in contrast, contains at its c a r b o x y t e r m i n u s a site that, w h e n
phosphorylated by GSK-3P, enhances the degradation of APC-bound p-catenin. 6 3 This site is almost
invariably lost in APC mutations (Fig 2, B), a fact that
may well correlate with the reportedly increased
expression of p-catenin in early colorectal adenomas. 64 Wnt-1 signaling inhibits GSK-3p phosphorylation of APC and results in cytoplasmic and nuclear
accumulation of p-catenin. 6 5 p-Catenin has been
171 Residues
Homo-oligomerization of
wild-type APC protein
Inactivating oligomerization
of wild-type with mutant protein
Truncation
Or
^
COOH
NH|
Nonoligomerization—caused by
loss of binding site In severely
truncated protein
Vk*»
WT-APC
B
NH2
"t>
Mutant APC
WTAPC
COOH
• p-catenin binding site (codons 1014 to 1210)
• Phosphorylation site—important in p-catenin degradation
(codons 1323 to 2075)
• Microtubule interaction site (terminal third)
• DLG and EB-1 binding sites
FIG 2. A, Negative regulatory effect of adenomatous polyposis coli
(APC) gene product on the cell cycle and loss thereof in truncating
mutations. B, Depiction of APC protein showing carboxy-terminal
binding sites for p-catenin, DLG, and EB-1 proteins, and microtubule interaction and phosphorylation site, all of which may be
lost in truncating mutations. Black bar = amino terminal portion of
protein; gray bar = carboxy terminal portion of protein in which
majority of truncating mutations occur.
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AMERICAN JOURNAL OF
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shown to interact with leukocyte enhancing factor
(LEF-1) and members of the T-cell factor (Tcf) family
of transcription factors. 66 It has been reported that
LEF-1 binds directly to p-catenin and translocates the
latter to the nucleus, 66,67 thus potentially mediating its
role in the Wnt-1 signaling pathway.
Constitutive complexing of P-catenin with Tcf-4
and LEF-1 has been reported in APC _//_ colorectal carcinoma cells (cell lines homozygous for the deletion
of APC) 68 and melanoma cell lines 69 and is believed
to be related to cancer progression through persistent
activation of as yet uncharacterized downstream target g e n e s . E x o g e n o u s w i l d - t y p e (WT)-APC can
down-regulate p-catenin and abrogate transcriptional
transactivation by removing P-catenin from Tcf in
APC"/ - cancer cells. 68 Thus, regulation of p-catenin
seems critical to APC function as a tumor suppressor
gene. This function can be disrupted by mutations in
APC or p-catenin 70 ; the latter have been reported in
colorectal carcinoma very infrequently. The carboxyterminus of the APC protein also contains binding
sites for EB-1 protein (of u n k n o w n function) and
DLG tumor suppressor protein (the human homologue of Drosophila disks larger tumor suppressor
protein) (Fig 2, B).71 The significance of these associations remains to be elucidated.
It has been shown that the WT-APC protein colocalizes with the microtubule cytoskeleton via its
carboxy-terminus. 72 Expression of partial cDNA constructs has indicated that the carboxy-terminus of
the protein is essential for this interaction, 7 3 and
notably, this region is lost in virtually all mutated
(truncated) APC products (Fig 2, B). The APC protein has been detected near the ends of microtubules
at the o u t e r m o s t p o i n t s of cell-cell c o n t a c t s . 7 4
W h e t h e r APC d i r e c t l y b i n d s m i c r o t u b u l e s or
whether other proteins link APC to the microtubules
remains to be established.
In the gut, where an intact epithelial monolayer must
be maintained in the face of rapid epithelial cell turnover
with progressive migration of cells from the depths of
crypts to the tips of villi, the balance between cell migration and cell-cell adhesion is critical. Accumulation of
excess epithelial cells at the crypt-villus junction produces a polyp. Considering this, with the knowledge
that truncated APC protein is causally linked to polyp
formation, the possibility that APC mutations may be
related to a disruption of the balance between cell
migration and cell adhesion becomes intriguing.
The interactions of APC and E-cadherin with pcatenin are a p p a r e n t l y separate, a n d it has been
reported that APC protein and E-cadherin compete
AJCP-
for P-catenin. 61 Other investigators considered this
implausible because the expression level of E-cadherin greatly exceeds that of APC, making competition unlikely, except p e r h a p s locally, where APC
tends to cluster near microtubules at the outer boundary of cell-cell contacts where cells are migrating past
one another. 74 It is possible that in this microenvironment, the functional APC protein, by decreasing the
availability of p-catenin to E-cadherin, could cause
localized loosening of cell-cell adhesive junctions,
resulting in the facilitation of cell migration. Loss of
such a function could then perhaps allow cells to
accumulate and "heap u p " into a polypoid mass.
The overexpression of full-length APC protein
reportedly blocks cell cycle progression from the
75
G Q / G J to S phase. This is thought to result largely
from inhibition of CDK2 (cylin-dependent kinase)
activity. Interestingly, C-terminally truncated mutant
APC proteins diminish the cell cycle-blocking activity
of w i l d - t y p e APC, possibly by i n a c t i v a t i n g heterodimerization (Fig 2, A). The exact mode of action of
APC in cell cycle r e g u l a t i o n is unclear, b u t it is
unlikely to be similar to the much-studied p53, pRB
(retinoblastoma) and Wilms' tumor-1 proteins, all of
which also have negative regulatory effects on cell
cycle progression from G Q / G J to S phase because these
are nuclear proteins and APC is a cytoplasmic protein.
The APC protein has been shown to associate with
microtubules and cell adhesion molecules to modify
transcriptional activation and to alter cell cycle regulation. Loss of functional APC could thus result in
impairment of cell migration, perhaps as a result of
stabilization of cell-cell adhesions as increased free
cytoplasmic P-catenin is incorporated into the E-cadherin-catenin unit. A simultaneous increase in cell
proliferation could further enhance accumulation of
cells at the crypt-villus boundary and result in polyp
formation, setting the stage for carcinogenesis.
It is hoped that the advances in our understanding
of the molecular pathology of FAP will ultimately
result in novel therapeutic strategies, as alluded to in
a rather amusing fashion by Dukes in his thoughtprovoking 1952 rhyme:
"You are old, Father William," the young surgeon said,
"And your colon from polyps is free.
Yet most of your sibling are known to be dead—
A really bad family tree."
"In my youth," Father William replied with a grin,
"I was told that a gene had mutated,
That all who carried this dominant gene
To polyps and cancer were fated.
1998
O'SULLIVAN ET AL
525
Familial Adenomatous Polyposis
"I s o u g h t advice from a surgical friend,
W h o sighed a n d s a i d — ' W i t h o u t d o u b t
Your only escape from a n u n t i m e l y e n d
Is to h a v e y o u r intestine right out.'
"It s e e m e d rather b a d luck—I w a s t h e n b u t n i n e t e e n —
So I w e n t a n d c o n s u l t e d a quack,
W h o t o o k a firm g r i p o n m y d o m i n a n t g e n e
A n d p r o m p t l y mutated it back."
"This," said the s u r g e o n , "is s o m e t h i n g q u i t e n e w
A n d before w e ascribe a n y m e r i t
We m u s t see if the claims of this fellow are true,
A n d observe w h a t y o u r children inherit!"*
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AJCP • May 1998