Influence of family history on penetrance of hereditary cancers in a population setting

Abstract

BackgroundWe sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. MethodsWe analysed 454,712 UK Biobank participants with exome sequence and clinical data. We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for age, sex, death, recruitment centre, screening and prophylactic surgery). ResultsWomen with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was significantly higher in those with a first-degree family history (relative hazard 10.29 and 7.82, respectively) than those without (7.82 and 4.66). Penetrance to age 60 was also higher in those with a family history (44.7% and 24.1%) versus those without (22.8% and 17.9%). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of bowel cancer that was significantly higher in those with a family history (relative hazard 63.7, 68.4 and 12.1) than those without (20.9, 18.6 and 5.9). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (27.1% and 25.2%) versus those without (15.2% and 3.2%). ConclusionsIndividuals with pathogenic cancer syndrome variants are at significantly less elevated risk of cancer in the absence of family history (risk ratio 0.57), so invasive follow-up may be unwarranted.