Multigene Panel Testing Provides a New Perspective on Lynch Syndrome

Abstract

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10^-5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10^-7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

Fig 1.

Overall mismatch repair gene and EPCAM mutation distribution (n = 579).

Fig 2.

Percentage of mutation carriers per mismatch repair gene compared with previous studies. The χ² test was used to compare mutation frequencies from this study with those from previous studies. Hampel et al, A^, is a population-based endometrial cancer cohort. Hampel et al, B^, is a population-based colorectal cancer cohort. Palomaki et al calculated a weighted proportion from four previous studies on colorectal cancer cohorts. Bonadona et al is a cohort of patients who were suggestive of Lynch syndrome (LS). Moreira et al includes patients from four large registries of population-based and/or high-risk families with colorectal cancer. Yurgelun et al is a cohort of patients with histories suggestive of LS. Sjursen et al is a cohort of individuals with a clinical diagnosis of hereditary nonpolyposis colorectal cancer and/or a molecular diagnosis of LS. The cohort in Møller et al is a pooled prospective database of individuals with LS from several collaborative groups. (*) EPCAM mutations were excluded for all comparisons except those with Møller et al. Most previous studies did not analyze EPCAM, but in Møller et al, EPCAM mutations were combined with MSH2 and could not be excluded. As a result, the number of patients for the comparison with Møller et al in this study is 579, and the MSH2 percentage for this study is 24.9 with EPCAM mutations included.

Fig 3.

Mismatch repair gene mutation distributions among tumor-specific subgroups. (A) Patients with breast cancer (BC) without ovarian cancer (OC), colorectal cancer (CRC), or endometrial cancer (EC; n = 63). (B) Patients with CRC without BC, EC, or OC (n = 144). (C) Patients with OC without BC, CRC, or EC (n = 40). (D) Patients with EC without CRC, BC, or OC (n = 71).