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
Toqir K Mukhtar, Naomi Wilcox, Joe Dennis, Xin Yang, Marc Naven, Nasim Mavaddat, John R. B. Perry, Eugene J. Gardner, Douglas F. Easton
Abstract
Background Deleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear. Methods Cancer associations for coding variants in ATM and CHEK2 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%). Results PTVs in ATM 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 CHEK2 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). Conclusion PTVs in ATM and CHEK2 are associated with a wide range of cancers, with the highest RR for pancreatic cancer in ATM PTV carriers. These findings can inform genetic counselling of carriers.