Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequenced data
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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, and require further investigation.
Methods
Cancer 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 <0·1%).
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 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 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.
WHAT IS ALREADY KNOWN ON THIS TOPIC
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While 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.
WHAT THIS STUDY ADDS
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We 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 .
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ATM PTVs 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.
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For CHEK2 PTVs, 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 POLICY
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ATM 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.
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The 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 .
