Protein-truncating and rare missense variants in <i>ATM</i> and <i>CHEK2</i> and associations with cancer in UK Biobank whole-exome sequence data.

Abstract

Deleterious germline variants in <i>ATM</i> and <i>CHEK2</i> have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear. Cancer associations for coding variants in <i>ATM</i> and <i>CHEK2</i> were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0.1%). PTVs in <i>ATM</i> were associated with increased risks of nine cancers at p<0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin's lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p<0.05: stomach, pancreas, prostate, Hodgkin's disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.PTVs in <i>CHEK2</i> were associated with three cancers at p<0.001 (breast, prostate, HD) and six at p<0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0.001: breast, prostate, LL; p<0.05: melanoma, multiple myeloma). PTVs in <i>ATM</i> and <i>CHEK2</i> are associated with a wide range of cancers, with the highest RR for pancreatic cancer in <i>ATM</i> PTV carriers. These findings can inform genetic counselling of carriers.