Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequenced data

BackgroundDeleterious germline variants in ATM and CHEK2 have 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 in ATM and CHEK2 were 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{middle dot}1%). ResultsPTVs in ATM were associated with increased risks of nine cancers at p<0{middle dot}001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia [LL]), and two at p<0{middle dot}05 (colon, diffuse non-Hodgkins lymphoma [DNHL]). Carriers of rMSVs had increased risks of four cancers (p<0{middle dot}05: stomach, pancreas, prostate, Hodgkins 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 in CHEK2 were associated with three cancers at p<0{middle dot}001 (breast, prostate, HD), and six at p<0{middle dot}05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0{middle dot}001: breast, prostate, LL; p<0{middle dot}05: melanoma, multiple myeloma). ConclusionPTVs 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. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIWhile previous research shows there is evidence for association between variants in ATM or CHEK2 and 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. C_LI WHAT THIS STUDY ADDSO_LIWe examined data from a large cohort study to derive relative and absolute risks for all cancer types for carriers of PTVs and rMSVs in CHEK2 and ATM . C_LIO_LIATM PTVs were associated with significantly increased risk for 11 of 23 sites examined (nine at p<0{middle dot}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{middle dot}5. C_LIO_LIFor CHEK2 PTVs, statistically significant risks were observed for seven of the 21 sites examined (one at p<0{middle dot}001). Carriers of rMSVs had increased risks of five cancers with the risk being highest for lymphoid leukaemia (approximately two-fold). C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIATM and CHEK2 are included on many cancer gene panels used in family cancer clinics, and the risk estimates from these analyses can inform genetic counselling for carriers. C_LIO_LIThe estimated absolute risks for pancreatic cancer in ATM PTV 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 include ATM . C_LI