Exploring the clinical significance of pathogenic variants in Lynch syndrome: A single-center retrospective review.

Abstract

e22657 Background: Lynch syndrome (LS) is the most common hereditary cancer syndrome and is associated with increased malignant risk due to four pathogenic variants in mismatch repair genes. Although population-level genomic studies identify PMS2 and MSH6 as the most frequent variants, MLH1 and MSH2 account for most pathogenic variants in LS families. Understanding variant-specific cancer risks may improve early detection of LS-associated malignancies. We report mutation patterns, demographic characteristics, and family history trends in a LS patient cohort. Methods: We retrospectively identified patients with germline mutations consistent with Lynch syndrome at an urban US academic medical center (N=70). Demographic characteristics, germline mutations as well as personal and family histories of malignancy were extracted from the electronic health record, summarized descriptively, and stratified by mutation type and race. Results: Our cohort’s mutation profile for MLH1, MSH2, MSH6, and PMS2 mutations was 20, 20, 23, and 26%. This was particularly driven by black patients (N=14) in whom 42% of pathogenic variants were PMS2. The incidence of cancer type was similar across demographic groups. 76% of PMS2 carriers in our cohort had a positive family history of breast cancer, with breast cancer representing 37% of all malignancies seen in families carrying a PMS2 mutation, more than any other malignancy. This trend was not seen in other mutations. Conclusions: We present a single institution retrospective analysis of LS patients. Mutation profiles have been seen to vary by population, with most studies evaluating prevalence of LS mutations in the general population while ours evaluates pathogenic variants in confirmed LS families. We found a comparatively increased prevalence of PMS2 and MSH6 mutations, particularly in black LS families. Breast cancer prevalence was increased in LS families carrying PMS2 mutation (not other LS families), notable given breast cancer is not commonly viewed as LS-associated. Our findings highlight the need for investigation into mutation profiles for confirmed LS families and a possible correlation between PMS2 and breast cancer. Cancer type Family history (N, %) MLH1 Colorectal (4) Colorectal (16, 67%)Gastric (5, 21%)Endometrial, pancreatic, urothelial (1, 4%) MSH2 Colorectal (2)Ovarian (2) EndometrialSmall intestine Colorectal (11, 34%)Urothelial (5, 16%)Endometrial (4, 13%)Gastric, pancreatic, ovarian (3, 9%)Small intestine, biliary, brain (1, 3%) MSH6 ColorectalEndometrial (3)Sebaceous epitheliomaUrothelial Endometrial (10, 29%)Colorectal (9, 26%)Urothelial (6, 18%)Pancreas (5, 15%)Ovarian, brain (2, 6%) PMS2 Colorectal (2)EndometrialGastricBreast (2) Colorectal (13, 50%)Endometrial (6, 22%)Ovarian, pancreatic, urothelial (2, 8%)Gastric (1, 4%)Breast (15)* *Not included in percentage calculations.