Investigating the Link between Lynch Syndrome and Breast Cancer

Abstract

Lynch syndrome is an inherited cancer-susceptibility disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. Historically known as hereditary nonpolyposis colorectal cancer, this syndrome is associated with increased risk for a multitude of cancers, including colorectal, endometrial, ovarian, small bowel, urothelium, biliary tract, and stomach (1-3). Lynch syndrome affects 1 in 279 individuals, and is more common than Hereditary Breast and Ovarian Cancer Syndrome caused by BRCA1 and BRCA2 mutations (4, 5). Lynch syndrome is also inherited in an autosomal dominant fashion. Recent studies have suggested that breast cancer may be included in the spectrum of Lynch syndrome-associated cancers, but the evidence is controversial. Cohort studies have found significantly increased age-specific incidence rate ratios of breast cancer in Lynch patients (6, 7). Case series have also shown high prevalence of breast cancer in Lynch populations, with earlier age of diagnosis compared to the general population (8). Investigators have looked at microsatellite instability, immunohistochemistry and mismatch repair gene deficiency in breast cancers of Lynch syndrome patients, suggesting that patients with Lynch syndrome are more likely to exhibit microsatellite instability and MMR protein loss compared with sporadic breast cancers (9-11). However, other studies show no association and recommend that increased surveillance is not indicated for Lynch syndrome patients (1,12,13).Multigene panel testing has provided new insight, suggesting that individuals with MSH6 and PMS2 mutations may have a higher risk for breast cancer (14,15). A case-control study published by Couch showed that only MSH6 mutations were associated with a statisti-

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

“…Consensus in the literature is that there is no statistically significant association between germline mutations in these MMR genes and breast cancer risk [ 53 ]. However, some studies do identify an increased risk of breast cancer incidence, and younger age at diagnosis in women with germline variants in PMS2 and MSH6, but no association with germline mutations in MLH1 or MSH2 [ 54 , 55 ]. A recent study conducted in a cohort of 711 patients with hereditary breast cancer, reported that 69 (9.7 %) patients had at least one germline mutation in the MMR genes.…”

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

“…The distribution of MMR gene pathogenic mutation in LS-CRC in China was as follows: MLH1 39.1 %, MSH2 33.9 %, MSH6 12.2 %, PMS2 9.6 % [ 4 ]. According to the studies from non-Asian population, MSH2 and MSH6 are the main susceptibility genes for ovarian cancer [ 25 ], MSH2 for urinary tract cancer [ 21 ], and PMS2 for breast cancer [ 26 ]. These LS-RC have not been fully studied in Asian population.…”

The Rare Diagnosis of Synchronous Breast and Colonic Cancers: A Case Report and Review of Literature

“…Some reports mentioned that LS is associated with a higher risk of breast cancer (up to two fold), in particular with MSH6 and PMS2 mutations as well as cases of MSI. The other observation is that age at diagnosis is younger in carrier cases with mismatch repair defects exhibited in the breast tumors [16][17][18]. Ford et al, in 2012, suggested a wider prospective study to assess if breast cancer is a component of LS as well as to evaluate the prognostic and predictive value of MSI in breast cancer management [16].…”