Original article—alimentary tract
Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer

https://doi.org/10.1016/j.cgh.2010.10.021Get rights and content

Background & Aims

Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC).

Methods

Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses.

Results

Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%–9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%–10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%–11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%–3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%–85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively.

Conclusions

In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.

Section snippets

Subject Population

Subjects were recruited through the Colon CFR, an international collaboration of 6 participating centers (University of Hawaii, Honolulu, HI; Fred Hutchinson Cancer Research Center, Seattle, WA; Mayo Clinic, Rochester, MN; University of Southern California Consortium, Los Angeles, CA; Cancer Care Ontario, Toronto, Canada; and University of Melbourne, Melbourne, Australia) organized in 1997 to create a comprehensive resource for genetic epidemiology studies. As described elsewhere,18 recruitment

Results

One hundred ninety-five subjects were included in the final analysis cohort, with 91 (47%) men and 104 (53%) women. The mean (standard deviation) age at CRC diagnosis was 42.9 (±6.1) years. Subject characteristics were similarly distributed across the 3 participating Colon CFR sites, with the exception of age at CRC diagnosis (Table 1).

Germline MLH1, MSH2, and MSH6 sequencing data were obtained for 195 (100%), 195 (100%), and 189 (97%) subjects, respectively. Specific MMR gene sequence

Discussion

In this multicenter study of young-onset CRC cases, direct germline analyses of MLH1, MSH2, and MSH6 yielded a prevalence of 5.6% for deleterious/suspected deleterious mutations. This study represents the description of non-triaged MMR gene testing in a North American, population-based sample of young-onset CRC cases. Encouragingly, our findings are consistent with results from a prior, population-based study in Scotland that reported an MMR gene mutation prevalence of 4.4% for CRC cases

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    Conflicts of interest The authors disclose the following: Dr Limburg served as a consultant for Genomic Health, Inc, from August 12, 2008, to April 19, 2010. The remaining authors disclose no conflicts.

    Funding Funding for and conduct of the gene mutation analyses were provided by Myriad Genetic Laboratories, Salt Lake City, UT. The Colon Cancer Family Registry is supported by NIH National Cancer Institute grants CA074783 (Ontario Registry for Studies of Familial Colorectal Cancer), U01 CA074800 (Mayo Clinic Cooperative Family Registry for Colon Cancer Studies), and U01 CA074799 (USC Familial Colorectal Neoplasia Collaborative Group), as well as U01 CA097735 (Australian Colorectal Cancer Family Registry), UO1 CA074794 (Seattle Colorectal Cancer Family Registry), and U01 CA074806 (University of Hawaii Colorectal Cancer Family Registry).

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