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Clin Genet 2005: 68: 80–87
Printed in Singapore. All rights reserved
Copyright # Blackwell Munksgaard 2005
CLINICAL GENETICS
doi: 10.1111/j.1399-0004.2005.00458.x
Short Report
Frequency of hereditary non-polyposis
colorectal cancer among Uruguayan patients
with colorectal cancer
Sarroca C, Della Valle A, Fresco R, Renkonen E, Peltömaki P, Lynch
HT. Frequency of hereditary non-polyposis colorectal cancer among
Uruguayan patients with colorectal cancer.
Clin Genet 2005: 68: 80–87. # Blackwell Munksgaard, 2005
Few studies have investigated the frequency of hereditary non-polyposis
colorectal cancer (HNPCC) in patients with colorectal cancer (CRC),
and these have shown marked geographic variations. The aim of this
study was to estimate the frequency of HNPCC in a cohort of
Uruguayan CRC patients. We included all patients operated consecutively for CRC in the Hospital Central de las Fuerzas Armadas
(Uruguay) between 1987 and 2003. Cases were classified into three
groups: (i) those fulfilling Amsterdam criteria; (ii) those not fulfilling
Amsterdam criteria but considered as a population at increased risk of
cancer; and (iii) sporadic CRC. Genetic analysis to detect point
mutations in hMLH/hMSH2/hMSH6 genes was performed in group 1
patients. Cases not showing mutations were tested by multiplex ligationdependent probe amplification. Among 461 patients, group 1
represented 2.6%, group 2 represented 5.6%, and sporadic cases 91.8%.
hMLH1/hMSH2/hMSH6 mutations were found in 25% of cases
classified as HNPCC (two in hMLH1 and one in hMSH2). No
mutations were detected in hMSH6 gene. The proportion of CRC
patients that fulfilled Amsterdam criteria agrees with other reports.
However, the percentage of HNPCC cases with identified mutations
(25%) may be lower than that reported from other populations. This
may reflect, among other possible causes, a different genetic profile in
the Uruguayan population.
Hereditary non-polyposis colorectal cancer
(HNPCC) is an autosomal dominantly inherited cancer syndrome characterized by a high risk and early
onset of colorectal cancer (CRC) and other related
cancers (e.g. endometrium, ovary, stomach, pancreas, small bowel, and uro-epithelial and biliary
tract cancers). This syndrome is expressed by genomic fluctuations, which results in microsatellite
instability (MSI) in the tumor tissue as a consequence
of germline mutations in DNA repair genes (1).
The molecular environment of HNPCC has been
recently clarified (2, 3). Defects in seven mismatch
repair genes (i.e. hMLH1, hMSH2, hPMS1,
hMSH2, hMSH6, hMLH3, and hMSH3) have
been associated with this syndrome
(4–8).
Mutations in hMSH2/hMLH1 account for the
80
C Sarrocaa, A Della Vallea,b,
R Frescob, E Renkonenc,
P Peltömakic and HT Lynchd
a
Uruguayan Collaborative Group: Survey
of Hereditary Oncologic Disorders,
Hospital Central de las Fuerzas Armadas,
Montevideo, Uruguay, bClinical Oncology
Department, Hospital de Clı́nicas,
Facultad de Medicina, Universidad de la
República, Montevideo, Uruguay,
c
Department of Medical Genetics,
Biomedicum Helsinki, University of
Helsinki, Helsinki, Finland, and
d
Creighton’s Hereditary Cancer Institute,
Department of Preventive Medicine,
Creighton University School of Medicine,
Omaha, NE, USA
Key words: frequency – hereditary nonpolyposis colorectal cancer – hMLH1 –
hMSH2 – hMSH6 – Uruguay
Corresponding author: Dr Adriana Della
Valle, Leyenda Patria 3038/102, 11300
Montevideo, Uruguay.
e-mail: [email protected]
Received 17 February 2005, revised and
accepted for publication 14 March 2005
majority of cases of HNPCC (5–8). These mutations
induce a generalized genomic instability, clearly evident in microsatellites (phenotype RERþ, replication errors) (9, 10), which is used to define these
defective genes. It has been shown in CRC patients
that they are associated with a longer survival time
than those not presenting this instability (11).
Susceptible individuals could clearly benefit from a
monitoring program for these genetic markers and
by the vigilance and monitoring of target organs.
Uruguay has an epidemiological behavior similar to that observed in countries in the developed
world. Cancer is considered as a major health
issue, because it is responsible for almost 25%
of deaths. Presently, the risk of developing CRC
is estimated at 5.8% at 70 years of age (12), and
Frequency of HNPCC in Uruguay
the same is observed in most Western industrialized countries. The incidence rates of CRC in
Uruguay are 33.83/100,000 for men and 26.31/
100,000 for women, while the mortality rates are
17.57/100,000 and 13.94/100,000, respectively. As
in many other countries, the actual incidence of
HNPCC is unknown.
The few epidemiological studies, which have
analyzed the frequency of HNPCC in patients
who have undergone surgery for CRC, showed
a marked geographic variability. The incidence of
this condition reported in international studies
has varied between 0.3 and 13% (13–22). This
variability may reflect on the strategies used for
follow-up and treatment. It appears that these
strategies must be tailored to the incidence of
this condition in each particular region (23–27).
For example, Cornaggia (15) states that ‘the data
underline the importance of a precise knowledge
of actual HNPCC incidence in different populations in order to optimize effectiveness and efficiency of screening programs for the disease’.
Our purpose is to estimate the frequency of
HNPCC among non-selected Uruguayan
patients having undergone surgery for CRC in a
single institution, by using the family history
approach, followed by genetic testing in families
suspected of having HNPCC.
Patients and methods
Patients
A retrospective analysis was performed on a sample of non-selected patients operated consecutively for CRC in the Central Armed Forces
Hospital (CAFH) of Montevideo, Uruguay.
Inclusion criteria were as follows: (i) histologically confirmed CRC; (ii) surgery performed in
the CAFH between January 1985 and January
2003; and (iii) completion of a registration chart
which included personal and family history of
cancer, polyps, and inflammatory bowel disease,
causes of morbidity and mortality of first- and
second-degree relatives, surgical procedures performed for CCR treatment in proband, surgical
findings, and pathology reports. All the data
were entered in a database using EPI-INFO 6.04c
(Centers for Disease Control and Prevention,
Atlanta, GA). After surgery, patients were followed as recommended (28). Informed consent
was obtained from all participants.
Description of the population
Uruguay has a total population of 3,163,763
inhabitants (29). The CAFH is responsible for
the care of 5% of the entire country population
(170,000 persons). Patients from all social levels,
residing in the capital city (Montevideo), in small
towns and in rural areas are treated in this
hospital.
Classification of patients according to family history
Each patient was included in one of the three
groups:
1. Group 1: those who fulfilled Amsterdam criteria I or II (Tables 1 and 2) categorized as
HNPCC (30, 31).
2. Group 2: those patients with a family history
of cancer for two consecutive generations and/
or a total of at least three relatives in the first
degree, not taking into account the site of the
tumor or age at diagnosis, as these were considered to be a population at increased risk of
cancer (PIR). They are defined as a subgroup
of the general population of a country or geographic region that – through several generations and because of genetic mechanisms – has
an increased incidence of cancer than that
calculated for the general population of the
respective region (32, 33). This group has an
elevated cancer aggregation but does not fulfill Amsterdam criteria I or II. The phenotypic
characteristics of the individuals, in connection with CRC, are similar to those of the
general population. However, through the
investigation of the family history, an
increased frequency of different types of cancer is found.
3. Group 3: this includes patients with sporadic
cancers who do not fulfill the above-mentioned criteria for groups 1 and 2.
For every patient in groups at increased risk
(1, 2), a new family protocol was opened, including
the following information: site of the tumor in
relative(s), age at the onset of CRC or other
HNPCC-related cancer in relative(s), the date of
birth and death of the individual(s), pathology
Table 1. Amsterdam criteria I (30)
There must be at least three relatives with colorectal cancer.
The following criteria must all be present:
One affected member directly related to two other affected
relatives
At least two successive generations must be affected
At least one individual diagnosed with colorectal cancer
before the age of 50 years
Familial adenomatous polyposis must be ruled out
Tumors must have pathologic confirmation
81
Sarroca et al.
Table 2. Amsterdam criteria II (31)
There must be at least three relatives with cancers associated
with HNPCC (colorectum, endometrium, small bowel, ureter,
or renal pelvis):
One affected member directly related to two other affected
relatives
At least two successive generations must be affected
At least one individual diagnosed before 50 years of age
Familial adenomatous polyposis must be ruled out
Tumors must have pathologic confirmation
HNPCC, hereditary non-polyposis colorectal cancer.
reports, endoscopic studies, institution where
they were admitted, and name of referring physicians. Detailed pedigrees were constructed for
each of the patients in groups 1 and 2.
Whenever a case of CRC or any other HNPCCrelated cancer in family members was reported,
this was confirmed by pathology reports. When it
was not available, we resorted to the death
certificate.
Mutation detection
Samples containing 20 ml of peripheral blood
drawn from all patients in group 1 (HNPCC) at
the CAFH were sent to P. Peltomäki. These
samples were first screened for possible point
mutations in the three major HNPCC-associated
genes hMLH1, hMSH2, and hMSH6. The first
two genes were analyzed by denaturing gradient
gel electrophoresis of genomic DNA (mainly) or
by the in vitro transcription and translation analysis of RNA, followed by automated sequencing
of genomic DNA in cases showing aberrant fragments. The methodology has been described previously (34, 35). hMSH6 was studied by direct
exon-specific sequencing using published primers
(36). Cases that did not show mutations were
tested for possible large deletions and amplifications by multiplex ligation-dependent probe
amplification (MLPA) (37), using kits (SALSA
P003 and SALSA P008) and protocols provided
by the manufacturer (MRC-Holland, Amsterdam,
The Netherlands).
Statistical analysis
Non-parametric tests were employed to compare
age medians between different groups.
Survival time was measured as the interval
between surgery and the day of death or last
control. Kaplan–Meier’s method was applied
for drawing and analyzing survival curves. The
log-rank test was used for univariate comparisons. SPSS software was used to perform these
calculations (version 11.0.1 for Windows, SPSS
Inc., Chicago, IL).
Results
This study sample comprised a total of 461
patients fulfilling the inclusion criteria: 251 men
and 210 women with a median age at diagnosis of
66 years (range: 18–96). No patients were
excluded, and the necessary forms were completed in all cases. In total, 12 cases [2.6%; 95%
confidence interval (95% CI): 1.1–4.1%] were
classified as HNPCC according to the abovementioned criteria, 26 cases as PIR (5.6%; 95%
CI: 3.5–7.7), and 423 as sporadic (91.8%; 95%
CI: 89.3–94.3). Table 3 summarizes the main
clinical and pathologic characteristics of the
patients included in the study.
Median age at diagnosis was 45 years (range:
26–65) for HNPCC (75% of this group were less
than 55 years of age), 70 years for PIR (range:
36–88), and 67 years (range: 18–96) for sporadic
cases. There was a statistically significant difference between median age of HNPCC and those
of the other two groups (p ¼ 0.0003). Sixteen
percent of the patients (95% CI: 14.85–17.50)
(74/461) were less than 50 years old. When considering only those patients younger than 50
years old (n ¼ 74), eight were classified as
HNPCC (10.8%; 95% CI: 3.8–17.8) and five as
PIR (6.8%; 95% CI: 1.00–12.6), whereas the
remaining 61 were sporadic cases.
Table 3. Summary of clinical and pathological characteristics according to group
Number
Median age
Colon affected
Dukes stage B
Five-year survival
Group 1 (HNPCC)
Group 2 (PIR)
Group 3 (Sporadic)
12 (2.6%)
45
9/12 (75%)
10/12 (83.3%)
11/12 (91.7%)
26 (5.6%)
70
15/26 (58%)
14/26 (53.8%)
17/26 (65.4%)
423 (91.8%)
67
254/423 (60%)
209/423 (49.4%)
252/423 (59.6%)
HNPCC, hereditary non-polyposis colorectal cancer; PIR, population at increased risk of cancer.
82
Frequency of HNPCC in Uruguay
Colon cancer represented 75% (9/12; 95% CI:
50.00–100.00) of tumors in patients classified as
HNPCC, 58% (15/26; 95% CI: 39.03–76.97) in
PIR, and 60% (254/423; 95% CI: 55.33–64.67) in
sporadic cases.
With regard to Dukes staging system modified
by Astler and Coller (38), a predominance of
stage B was observed in HNPCC, representing
83.3% (10/12; 95% CI: 65.64–100.00) of all cases.
In the PIR group, 14 patients were of stage B
(53.8%; 95% CI: 34.2–72.96) and 209 in the
group 3 (49.4%; 95% CI: 44.64–54.16).
Five-year survival rates for the different groups
were 91.7% (11/12; 95% CI: 76.09–100) for
HNPCC, 65.4% (17/26; 95% CI: 47.11–83.63)
for PIR, and 59.6% (252/423; 95% CI: 54.92–
64.28) for sporadic cases. Table 4 summarizes
mean survival according to Dukes stage for
each group of patients, whereas Fig. 1 shows
survival curves for patients whose tumor were
staged as Dukes B and C.
In two of the 12 cases classified as HNPCC
(16.6%), a germline mutation in hMLH1 gene
was found (deletion resulting in a frameshift
and a premature stop codon -codon 228-).
These two patients were cousins (family no.
4082) and were affected by the same mutation,
as has been previously reported by us (Fig. 2)
(34, 39). Both patients are undergoing a strict
follow-up protocol and have presented no malignancies in more than 5 years. In another patient,
member of family no. 8161, a nonsense mutation,
R406X, in hMSH2 was found (Fig. 3). No mutations were detected in hMSH6 gene. Finally, no
deletions were found using MLPA.
Table 4. Mean survival in each group according to Dukes
stage
Dukes A
HNPCC
PIR
Sporadic
Dukes B
HNPCC
PIR
Sporadic
Dukes C
HNPCC
PIR
Sporadic
Dukes D
HNPCC
PIR
Sporadic
Mean survival
95% CI
No patients
All alive
157.55
128.00–187.10
All alive
150.21
140.48
110.71–189.71
128.20–152.75
All alive
83.21
123.91
55.09–111.32
107.49–140.34
Alive
All alive
48.49
33.75–63.23
HNPCC, hereditary non-polyposis colorectal cancer; PIR,
population at increased risk of cancer.
Discussion
This is the first South American study analyzing
the frequency of HNPCC in patients with CRC,
by means of a clinical evaluation as well as
genetic studies in patients fulfilling Amsterdam
criteria for this condition.
Of the 461 patients included, 16% (n ¼ 74) were
less than 50 years old; this is greater than the
percentage reported for the entire Uruguayan
population in the 2-year period between 1996 and
1997, in which for all cases of CRC, 7.9% were
below 50 years of age (40). Seventy-five percent (9/
12) of patients classified as HNPCC were less than
55 years old. This supports the finding that age is
an important factor for increased risk of HNPCC.
Therefore, it is critical to obtain a detailed family
history in young patients with CRC.
There is marked geographic variability in the
results of studies investigating the frequency of
HNPCC in patients having undergone surgery
for CRC in that its incidence have ranged from
0.3 to 13% (13, 22). These studies differ in methodological design, inclusion and exclusion criteria,
and methods for detecting mutations, all
of which may partially explain the observed differences. All of these studies have estimated the
frequency of HNPCC in consecutive cases of
CRC based on family history. In many of these
studies, no molecular analyses were performed
for hMLH1, hMSH2, and/or hMSH6 gene mutation detection. For instance, Evans et al. (13)
studied 1137 consecutive patients with CRC, of
which only 0.3% fulfilled Amsterdam criteria
and another 1.4% fulfilled less stringent criteria.
Reliability of family histories in retrospective
studies with long observational periods can be
called in question, and in part it depends on
how researchers confirm the data of interest (in
this case colorectal and other HNPCC-related
cancers in relatives). In our study, during the
15-year inclusion period, all cases were treated,
followed, and analyzed by the same group of
investigators; every diagnosis of CRC or other
HNPCC-related cancer was confirmed by pathology report, and if this was not possible, by the
death certificate. In Uruguay, death certificates
are easily available for researchers, making it
simple to verify the cause of death of all relatives,
in case pathology report was not available.
About 2.6% of all surgical patients with CRC
in our study fulfilled Amsterdam criteria; this
agrees with the frequency observed by other
authors (Table 5) (13, 22).
Although variations in the estimated frequency
of HNPCC based only on family history may
reflect true differences in the populations studied,
83
Sarroca et al.
DUKES C
DUKES B
1.1
1.1
Group 1 : HNPCC
Group 1 : HNPCC
1.0
1.0
.9
.9
Group 2 : PIR
.7
.8
Group 3 : sporadic
Cum Survival
Cum Survival
.8
.6
.5
Group 3 : sproadic
.6
.5
.4
.4
.3
.3
.2
.2
.1
.1
0.0
Group 2 : PIR
.7
0.0
0
100
50
150
200
Months
250
0
50
100
150
200
Months
Fig. 1. Survival curves for patients with stages B and C colorectal cancer (mean survival times and 95% CI in Table 4).
HNPCC, hereditary non-polyposis colorectal cancer; PIR, population at increased risk of cancer.
they may also be the result of differences in the
degree of certainty required by researchers to
confirm every diagnosis of CRC in the family
members. The performance of genetic studies in
patients fulfilling Amsterdam criteria may attain
greater certainty with regard to the true frequency of HNPCC caused by mutations in
hMLH1, hMSH2, and hMSH6 genes.
Despite the use of a comprehensive methodology for mutation detection covering point mutations and large rearrangements in the three major
HNPCC-associated genes, our study detected
germline mutations only in 25% (3/12) of
patients classified as HNPCC according to
Amsterdam criteria, which represent 0.6% of all
CRC patients included. While the proportion of
Male Female
Not affected
Affected
Dead
Mutation detected
Proband
Fig. 2. Genealogy of family no. 4082. A mutation in hMLH1 was found in two of its members (cousins).
84
Frequency of HNPCC in Uruguay
Male
Female
Not affected
Affected
Dead
Mutation detected
Proband
Fig. 3. Genealogy of family no. 8161, where a mutation in
hMSH2 gene was found.
mutations detected is clearly lower than that
reported in studies using MSI testing or DNA
mismatch repair protein expression for preselection (up to 70%) (41, 42), our figure may or may
not differ from studies using the fulfillment of
Amsterdam criteria alone as the starting point
(25–60%) (43–48). This difference could reflect
a differing genetic profile in the Uruguayan
population compared with other published studies. However, this would not be expected
Table 5. Comparison of our results with similar studies evaluating frequency of hereditary non-polyposis colorectal cancer (HNPCC) based on Amsterdam criteria and population at
increased risk of cancer (PIR) or similar, in patients having
undergone surgery for colorectal cancer
Reference
n
HNPCC
PIR or similar
Katballe et al. (1)
Evans et al. (13)
de Leon et al. (2)
Aaltonen (14)
Cornaggia et al. (15)
Sarroca (present study)
1200
1137
1721
509
197
461
20 (1.7%)
3 (0.3%)
45 (2.6%)
10 (2%)
1 (0.5%)
12 (2.6%)
–
16 (1.4%)
79 (4.6%)
–
–
26 (5.6%)
considering that the Uruguayan population is
composed predominantly of people of Spanish,
Italian, French, and Portuguese origin (49), and
most of the studies evaluating hMLH1 and
hMSH2 gene mutations in patients with CRC
were conducted in Europe. Besides, it must be
considered that this is a hospital-based series
and it may not reflect the actual frequency of
HNPCC throughout Uruguay.
The high frequency of cases fulfilling Amsterdam
criteria but with no mutations in the above-mentioned genes may be the result of random family
aggregations, shared environmental carcinogens,
unusual types of mutations not detectable by the
present methods, or mutations in other genes
which were not studied. Some authors have suggested that most families fulfilling Amsterdam criteria and presenting an aggregation of left colon
tumors and/or absence of multiple HNPCCrelated cancers have a lower probability of presenting mutations in the genes studied than those with
a predominance of right colon tumors and/or presence of other cancers related to HNPCC (1). In
our study, all patients with detected mutations
presented tumors of the right colon, and the same
propensity for tumors in that site was observed in
other affected members of family no. 4082, in
which right colon cancers where diagnosed in
68.6% of all cases (24/35 CRC). It is likely that
families who met Amsterdam criteria with predominance of left-sided colon cancer and without
other HNPCC-related cancer, fulfilled the criteria
due to other causes than mutations in hMLH1,
hMSH2, or hMSH6.
The estimated proportion of CRC attributable
to HNPCC due to mutations in mismatch repair
genes may be an underestimate of the actual
proportion of this condition in the population
studied. Using Bethesda criteria for categorizing
CRC patients (50) would have led us to perform
molecular analysis in a large number of patients
due to the wider inclusion criteria of this system,
and therein, it could have resulted in more
families with detected mutations. Some
hMLH1/hMSH2/hMSH6 mutation carriers
could have been identified among families who
did not met the Amsterdam criteria but belonged
to the PIR group, if we had performed molecular
analyses in this group. These cases would have
been categorized as HNPCC. However, we must
not expect a large number of mutation carriers
among families not categorized as HNPCC based
on the family history (1). Besides, the identification of new mutants would not have been possible in our study.
When interpreting our results, the low number
of cases in the HNPCC group must also be
85
Sarroca et al.
considered, because additional cases could have
had a great effect on the results. We expect to
continue including cases in the future in order to
enlarge the series.
In addition to the 2.6% of patients included in
group 1, another 5.6% were classified as PIR –
patients not fulfilling Amsterdam criteria but
presenting a significant family accumulation of
CRC. In these cases, molecular studies were not
performed. If both groups (HNPCC and PIR)
are considered as having an increased risk for
developing cancer, 8.2% of patients included in
this study may be considered as carriers for an
increased family risk of CRC.
The favorable prognoses found in HNPCC
patients agree with other studies (51, 52). This
outcome may be independent of the pathologic
characteristics of the tumor. This indicates that
the early detection of this group of patients is an
important issue because it may change the treatment strategy (53, 54).
In conclusion, we have presented the only existing South American study thus far that estimates
the frequency of HNPCC patients having undergone surgery for CRC. This estimation was based
on clinical criteria as well as molecular studies of
patients fulfilling Amsterdam criteria. While the
percentage of cases fulfilling these criteria was
similar to that observed in other studies, the
percentage of patients with germline mutations
in DNA mismatch repair genes may be lower
than that reported from other populations,
which needs to be examined further by additional
investigations.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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