Abstract
PurposeAn association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually. MethodsWe conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data). ResultsWhen evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56–2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17–3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42–1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72–2.06). ConclusionOur data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Highlights
Germ-line pathogenic variants (PVs) in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, and 3′ deletions of EPCAM, a gene just upstream of MSH2, cause Lynch syndrome (LS)
PMS2 (SIR = 2.92; 95% confidence interval (CI), 2.17–3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% confidence intervals (95% CI), 0.42–1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72–2.06)
Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer
Summary
Germ-line pathogenic variants (PVs) in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, and 3′ deletions of EPCAM, a gene just upstream of MSH2, cause Lynch syndrome (LS). There is evidence that cancer risk depends on the affected gene. The MMR pathway is responsible for repairing single base pair mismatches and small insertions or deletions that occur when DNA polymerase attempts to replicate small repeat sequences. Pathogenic variants within the MMR genes result in errors in DNA repair, leading to an increased mutation load in MMR-deficient cells.[1] Screening for MMR deficiency by microsatellite instability and immunohistochemistry assays is often performed on colorectal and endometrial tumors to identify patients with LS. Screening for MMR deficiency in breast tumors is currently not standard clinical practice, multiple studies have shown that breast cancers from women with LS are more likely to exhibit microsatellite instability and loss of one or more MMR proteins via immunohistochemistry, compared with sporadic breast cancers.[3,4,5,6,7,8,9,10,11,12,13,14]
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