Abstract
We investigated the prevalence of rare inherited pathogenic variants (PV) in 19 cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and their association with the risk of lymphoid malignancies (LM) overall and by common lymphoma subtypes and multiple myeloma. The study population included newly diagnosed LM cases (N = 6990) and unrelated controls (N = 42,632), excluding individuals with a history of hematologic malignancy. Whole exome sequencing was performed on DNA from whole blood. PV were defined as loss-of-function (i.e., nonsense, frameshift, consensus splice sites) or identified as "pathogenic" or "likely pathogenic" in the ClinVar database. A total of 1816 (3.7%) individuals had a PV across the 19 genes, higher in cases (4.7%) than controls (3.5%). In controls, CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the highest prevalence. ATM (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.36-2.49), CHEK2 (OR = 1.74, 95% CI: 1.42-2.13) and TP53 (OR = 9.07, 95% CI: 4.51-18.87) were associated with increased risk of LM overall and were further validated in the UK Biobank. We observed heterogeneity in associations by LM subtype. These results demonstrate that several commonly tested cancer predisposition genes are associated with an increased risk of LM.