Protein-truncating and rare missense variants inATMandCHEK2and associations with cancer in UK Biobank whole-exome sequenced data

Abstract

SummaryBackgroundDeleterious germline variants inATMandCHEK2have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear, and require further investigation.MethodsCancer associations for coding variants inATMandCHEK2were evaluated using whole-exome sequenced 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%).ResultsPTVs inATMwere associated with increased risks of nine cancers at p<0·001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia [LL]), and two at p<0·05 (colon, diffuse non-Hodgkin’s lymphoma [DNHL]). 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 CADD score in the highest quintile.PTVs inCHEK2were 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).ConclusionPTVs inATMandCHEK2are associated with a wide range of cancers, with the highest RR for pancreatic cancer inATMPTV carriers. These findings can inform genetic counselling of carriers.WHAT IS ALREADY KNOWN ON THIS TOPICWhile previous research shows there is evidence for association between variants inATMorCHEK2and multiple cancer types in individual smaller studies, the associations have not been consistently evaluated across all cancer types and, with the exception of breast cancer, the strengths of association are unclear.WHAT THIS STUDY ADDSWe examined data from a large cohort study to derive relative and absolute risks for all cancer types for carriers of PTVs and rMSVs inCHEK2andATM.ATMPTVs were associated with significantly increased risk for 11 of 23 sites examined (nine at p<0·001), with the relative risk being highest for pancreatic cancer (approximately seven-fold). Carriers of rMSVs had increased risks of four cancers, with a RR of approximately 1·5.ForCHEK2PTVs, statistically significant risks were observed for seven of the 21 sites examined (one at p<0·001). Carriers of rMSVs had increased risks of five cancers with the risk being highest for lymphoid leukaemia (approximately two-fold).HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYATMandCHEK2are included on many cancer gene panels used in family cancer clinics, and the risk estimates from these analyses can inform genetic counselling for carriers.The estimated absolute risks for pancreatic cancer inATMPTV carriers (11% in males and 8% in females by age 85) are notably higher than for other major pancreatic susceptibility genes including BRCA2, CDK2NA, and PALB2. Our findings can also inform NICE guidelines for pancreatic cancer, which do not currently includeATM.