Familial burden and other clinical factors associated with various types of cancer in individuals with Lynch syndrome

Background & Aims Lynch syndrome (LS) is associated with increased risks of various gastrointestinal, gynecologic, genitourinary, and other cancers. Many clinical practice guidelines recommend that LS carriers’ screening strategies be devised based on their family history of various cancers, in addition to age-/sex-/gene-specific considerations. The aim of this study was to examine the association between family history and other clinical factors with LS carriers’ histories of various cancers. Methods Two cohorts of LS carriers were analyzed: a laboratory-based cohort of consecutively-ascertained individuals undergoing germline LS testing and a clinic-based cohort of LS carriers undergoing clinical care at an academic medical center. Multivariable logistic regression was performed to assess clinical factors associated with LS carriers’ histories of various cancers/neoplasms. Familial burden was defined as LS carriers’ aggregate number of first-/second-degree relatives with a history of a given malignancy. Results Multivariable analysis of the laboratory-based cohort (3828 LS carriers) identified familial burden as being incrementally associated with LS carriers’ personal history of endometrial (OR 1.37 per affected first-/second-degree relative; 95% CI 1.21-1.56), urinary tract (OR 2.72; 95% CI 2.02-3.67), small bowel (OR 3.17; 95% CI 1.65-6.12), gastric (OR 1.93; 95% CI 1.24-3.02), and pancreaticobiliary cancers (OR 2.10; 95% CI 1.21-3.65) and sebaceous neoplasms (OR 7.39; 95% CI 2.71-20.15). Multivariable analysis of the clinic-based cohort (607 LS carriers) confirmed a significant association of familial burden of endometrial and urinary tract cancers. Conclusions Familial burden – in addition to age, sex, and gene – should be used to assess LS carriers’ risks of specific cancers and guide decision-making about organ-specific surveillance.