Affiliations of authors: D. J. Peel, A. Ziogas, M. Gildea, B. Laham, E. Clements, H. Anton-Culver, Epidemiology Division, Department of Medicine, University of California, Irvine; E. A. Fox, Dana-Farber Cancer Institute, Boston, MA; R. D. Kolodner, Ludwig Institute for Cancer Research, University of California School of Medicine, San Diego.
Correspondence to: Hoda Anton-Culver, Ph.D., Epidemiology Division, Department of Medicine, 224 Irvine Hall, University of California, Irvine, Irvine, CA 92697-7550 (e-mail: hantoncu{at}uci.edu).
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ABSTRACT |
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INTRODUCTION |
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Two major forms of hereditary colorectal cancer have been described: adenomatous polyposis coli (APC) and hereditary nonpolyposis colon cancer (HNPCC) (1215). Colorectal carcinoma develops in nearly all patients with dominantly inherited APC and its variants (16,17). HNPCC is much more common than APC. HNPCC has been operationally defined by the Amsterdam criteria: presence of colorectal cancer in at least three blood relatives in two consecutive generations who are first-degree relatives of each other and one colorectal cancer diagnosed before 50 years of age (12). HNPCC has been estimated to cause 3%4% of all colorectal cancers, although estimates range from fewer than 1% to 30% (1,2,7,9).
Several studies (1821) have shown HNPCC to be caused by inherited defects in genes encoding components of a DNA mismatch repair pathway. MSH2 or MLH1 germline mutations have been found in up to 70% of selected families with HNPCC (2224). A few non-HNPCC families and sporadic colon cancer case subjects have also been found to have a germline MSH2 or MLH1 mutation, but the frequency of such mutations within the general population is unknown (25,26).
The finding of microsatellite instability in colon cancer specimens was critical to cloning of the MSH2 and MLH1 genes (2730). However, reported microsatellite instability frequencies are inconsistent and have been difficult to interpret (29,3135). Methodologic issues arise from the choice of loci and from differing numbers of markers examined by individual investigators.
The purpose of this report is to present data on the proportion of HNPCC families in a population-based series of colorectal cancer. We also present data on the association between MSH2 or MLH1 mutations and microsatellite instability results in HNPCC families selected with the use of the Amsterdam criteria. In addition, we have attempted to further define the family history data for the Amsterdam criteria-defined HNPCC families selected from a population base.
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SUBJECTS AND METHODS |
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Probands were identified through the population-based cancer registries of the Cancer Surveillance Program of Orange County/San Diego Imperial Organization for Cancer Control. A letter was sent to physicians notifying them that their patients would be contacted regarding study participation. This letter was followed by a letter of introduction sent to the patient and a telephone interview with the patient regarding family history of cancer.
The population sampling was done with a stratification to increase the proportion of patients below age 65 years and, at the same time, to maintain the population-based status. All case subjects with colorectal cancer (probands) diagnosed (at all ages) in Orange County, CA, in 19941996 were ascertained. We also ascertained all case subjects diagnosed below age 65 years in San Diego and Imperial Counties, CA, in 1994 and 1995. A total of 2489 case patients were ascertained. Of these, 2137 were eligible for the study (alive at the time ascertained and having a contact address). The physician denied permission to contact 18 of the patients. From the 2119 case subjects contacted, 1433 agreed to participate in the study, which corresponds to a participation rate of approximately 70%. For the current analysis, we included all of the 1994 population-based case subjects from Orange County (n = 556) and case subjects below age 65 years from Orange County in 1995 and 1996 and from San Diego and Imperial Counties in 1994 (n = 578). Therefore, the total number of case subjects used in this report is 1134. The other 299 case subjects were not included in this analysis because they represented a partial population-based ascertainment and were 65 years old or older. Probands signed a consent form (Institutional Review Board No. 93*257) allowing the drawing of blood and the release of medical information, including access to pathology reports and tissue blocks.
Probands were classified as being either family history positive or family history negative. A positive family history was defined as having at least one first-degree relative with colorectal cancer or no first-degree relative with colorectal cancer and at least two maternal or two paternal second-degree relatives with colorectal cancer. The Amsterdam criteria (12) were used to define HNPCC families. In addition, we compared 11 HNPCC case subjects ascertained by community referral with the population-based sample. Genotyping for MSH2 and MLH1 and microsatellite instability analysis were done for nine families from this referral group for whom blood samples and tissue blocks were available.
Microsatellite Instability Analysis
Five markers for microsatellite instability analysis (ACTC, APC, TP53, D1S228, and D18S34) were chosen from commonly used dinucleotide markers. Five additional markers were chosen to provide a cross-section of microsatellite markers: dinucleotide (D15S11, D20S194, and D11S787), trinucleotide (D5S556), and tetranucleotide (D21S11).
Paraffin-embedded tissues were sectioned (10 µm), and tumor and normal tissues were delineated by a pathologist. Areas of normal and tumor tissues were microdissected from the delineated sections, and DNA was extracted by microwave treatment in a Tris (pH 8) buffer, removal of the melted wax after cooling, and then proteinase K treatment at 55 °C for 2 hours. Next, the samples were heat-treated at 95 °C for 5 minutes to inactivate the enzyme, and these were used as the template DNA. Amplification was performed with fluorescently labeled primers. The labeled products were run on an ALF DNA sequencer (Pharmacia Biotech, Inc., Piscataway, NJ), where the products were detected and compared with labeled size fragments. Samples were considered positive for microsatellite instability when at least two of 10 markers showed expansion in the tumor tissue.
MSH2 and MLH1 Sequencing
DNA was extracted from blood samples taken from probands with the use of a resin column procedure (Qiagen, Inc., Valencia, CA). Individual exons of MLH1 and MSH2 and the flanking intronic sequences were amplified and sequenced on an ABI 377 DNA sequencer (Applied Biosystems, Foster City, CA) as described previously (36,37), except that the polymerase chain reaction (PCR) primers were modified as required to eliminate the need for multiplex PCR.
Statistical Analysis
Proportions and 95% confidence intervals (CIs) were computed by exact binomial probabilities. Comparisons of proportions were made with the use of Fisher's exact test with a two-sided significance level of .05.
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RESULTS |
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Of the 1134 probands under study, 907 were classified as having a negative family history of colorectal cancer and 227 were classified as having a positive family history. Among the probands diagnosed in Orange County during 1994 (population-based sample, all ages), five (0.9%; 95% CI = 0.3%2.1%) were consistent with the Amsterdam criteria for HNPCC. Among the probands diagnosed at less than 65 years, 16 (2.1%; 95% CI = 1.2%3.4%) were consistent with the Amsterdam criteria for HNPCC (Table 1). All HNPCC case subjects identified were from the group under 65 years of age (mean age ± standard deviation = 52 years ± 9.2 years). The frequency of HNPCC among probands with a positive family history was 10.6% (95% CI = 6.2%16.6%). The sex and ethnicity of the participants are given in Table 2
. One proband was clinically diagnosed with familial adenomatous polyposis (FAP), for a frequency of 0.0013 from the population base.
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Other notable features of HNPCC-related tumors are the preferential proximal location of these tumors (38,39). However, in the sample from our population data, only four (25%) of 16 probands had a proximal tumor and nine (56%) of 16 had tumors localized in the rectum or the rectosigmoid (Table 3). In the referral case subjects, three (27%) of 11 probands had rectal or rectosigmoid tumors, which is comparable to rates for non-HNPCC tumors seen in this study and from the general population (38).
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MSH2 and MLH1 Sequencing and Microsatellite Instability Analysis in Referral Case Subjects With HNPCC
Referral HNPCC case subjects were evaluated with microsatellite instability analysis and MSH2 and MLH1 sequencing. Four of these kindreds were identified as microsatellite instability positive, and three of these were shown to have mutations in MSH2 and MLH1. One case subject was not evaluated for microsatellite instability but did have a nonsense mutation in the hMLH1 gene. The two mutations in MLH1 were both truncating and, therefore, were expected to be pathogenic. The two mutations in MSH2 were predicted to cause missense changes in positions conserved in Mus, Rattus, Xenopus, Arabidopsis, and Saccharomyces cerevisiae and, therefore, likely to disrupt MSH2 function.
It has been shown that the types of tumors within the family and the location of the tumors are different for subjects with MSH2 mutations compared with subjects with MLH1 mutations (38). The prevalence of rectal tumors is higher in MSH2 mutation subjects than in MLH1 mutation subjects (38). In the samples in which we have identified mutations, three of the five mutations identified occurred in MSH2, which may account for the higher proportion of rectal cancers observed in our series. It has also been shown that the types of tumors in HNPCC kindreds differ when the mutation occurs in different mismatch repair genes.
We found four HNPCC kindreds with microsatellite instability-positive phenotypes, and three of these had mutations in MSH2 or MLH1. Another five kindreds meeting the Amsterdam criteria failed to show a microsatellite instability phenotype and also failed to reveal any mutations in MSH2 or MLH1. Therefore, it would seem that, within the criteria used to define HNPCC kindreds, only a subset (approximately 45%) actually showed the molecular defect behind the cancer syndrome in this series. This observation differs from the findings from another study (40), in which a much higher proportion of HNPCC kindreds showed a microsatellite instability phenotype as well as MSH2 or MLH1 mutations.
To refine the criteria for HNPCC diagnosis, we looked further into the kindreds analyzed to see if there were other criteria that might help distinguish HNPCC families in which a mutation has been found from those families in which a mutation has yet to be found. Two of the mutations found appear in the mutation database of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (41). The rest of the changes appeared to be novel. Mutations tend to be specific to each kindred and can occur anywhere along the gene, although founder mutations have been found in some populations (42). In total, five families in our sample were found to have germline mutations in MSH2 or MLH1; three had them in MSH2, and two had them in MLH1. The data in Table 4 show that the average age at diagnosis ± standard deviation for probands from mutation-positive families was 46 years ± 9.73 years, whereas it was 69.6 years ± 16.26 years for those from mutation-negative families. Among mutation-positive probands, four in five had multiple primary cancers; in contrast, among mutation-negative probands, three in six had multiple primary cancers.
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DISCUSSION |
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In the cancer series identified from the population base, 0.9% met the strict Amsterdam criteria for HNPCC. Estimates of the prevalence of HNPCC vary from fewer than 1% (43) to as much as 13% (39). A study of data collected from a series of consecutive patients at a district hospital over a 14-year period (44) showed that only three (0.3%) fulfilled the Amsterdam criteria for HNPCC. Another population-based study (45) has found 3%5% of colorectal cancers due to Amsterdam-defined HNPCC. In another population study from a survey of microsatellite instability in 509 consecutive patients (46), seven families (1.3%) fulfilled the Amsterdam criteria, and a total of 10 (2%), including the seven Amsterdam criteria families, were found to carry germline mutations in MSH2 or MLH1. In our database seriesfrom a larger and different populationwe found a similar percentage (0.9%) of HNPCC families. The population studied by Aaltonen et al. (46) was drawn from the Finnish cancer registry; five of the 10 germline mutations discovered were founder mutation 1 of MLH1, found in the Finnish population (42). This finding raises the question as to the relevance of this population for drawing comparisons with other populations where no such founder mutation has yet been discovered. In the populations from Orange, San Diego, and Imperial Counties, there were many other families that may be classified as HNPCC families but that do not meet the full Amsterdam criteria but may meet other, less restrictive criteria, such as the Bethesda guidelines (47). Indeed, we identified approximately 86 families that may meet these criteria but not the Amsterdam criteria, and these families remain suspicious for HNPCC status. The prevalence of germline mutations in these families is unknown, but it is likely to be low. In one study looking at families that were suggestive of HNPCC families but that failed to meet the Amsterdam criteria (48), the prevalence of germline mutations was only 8% . In the same study, the prevalence of mutations in Amsterdam criteria families was 49%, similar to the percentage from our study.
Features of HNPCC Kindreds
Characteristics of subjects with HNPCC in our population included the presence of endometrial and ureteral cancers and increased mucinous tumor phenotype. Cancer of the ureter appeared to be strongly related to HNPCC status. Both colorectal and genitourinary tumors have been associated with the MuirTorre syndrome (49). The pedigree in our study that contained two family members with cancer of the ureter may be a candidate for this syndrome; however, no skin cancers were seen in this family (50). One of the other characteristics of HNPCC tumors, i.e., the prevalence of proximal tumors (39), was not seen in this group. Indeed, there was a prevalence of tumors of the rectum and rectosigmoid, which accounted for 56% of the tumors in the HNPCC group, whereas the referral group had 31% rectal cancer. Rectal cancers may not be diagnosed as HNPCC cases because of the assumed prevalence of proximal tumors among such cases, which may not be true when cases are ascertained from a population-based cancer registry.
Half of the probands fulfilling the Amsterdam criteria in our study showed a positive microsatellite instability status and mutations in MSH2 or MLH1. This prevalence is similar to another study (48), in which 50% of Amsterdam criteria families were shown to have germline mutations in MSH2 or MLH1. When these mutation-positive families are investigated further, it appears that they can be distinguished from non-mutation families on the basis of a number of criteria from their family history. These criteria include the presence of multiple primary cancers, either in the proband or in first-degree relatives, and an earlier age of onset, showing that there may well be a heterogeneity in the population of HNPCC patients.
In this study, the prevalence of Amsterdam criteria-defined HNPCC was 0.9%. Among probands under 65 years of age, the frequency of HNPCC was 2.1%. We realize that there may well be other families in the population that could in the future be classified as HNPCC families on the basis of molecular characterization. To our knowledge, this is the only study of a population group of colorectal cancer case subjects that has been stratified by age and that gives the incidence figures for HNPCC.
The other conclusion that can be drawn from these data is that some characteristics of HNPCC, such as the proximal location of tumors in the syndrome, may not always hold true in a population-based sample. The number of HNPCC cases is too small to compare the proximal location of tumors between the HNPCC group and all cases. However, the large numbers of non-HNPCC familial and sporadic cases ascertained in the same way allow stronger (in some ways) and more valid comparisons among the groups than in many previous studies.
This report is a first description of the colorectal cancer study that we are conducting. As such, it provides a broad description of colorectal cancer case subjects with regard to family history and gives a prevalence figure for HNPCC based on clinical data. We acknowledge that this is not the final answer for HNPCC prevalence figures in the general population; however, it is a necessary first step and provides general data for the scientific community. We hope that we will be able to complete a full molecular analysis in the near future.
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NOTES |
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We thank Dr. Frederick P. Li (Dana-Farber Cancer Institute, Boston, MA) for his helpful comments in the preparation of this manuscript and Sue Henger (University of California, Irvine, Epidemiology Division) for editorial assistance.
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Manuscript received December 9, 1999; revised July 12, 2000; accepted July 17, 2000.
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