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. 2024 Oct 23;61(11):1016-1022.
doi: 10.1136/jmg-2024-110127.

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

Toqir K Mukhtar  1   2 , Naomi Wilcox  3 , Joe Dennis  3 , Xin Yang  3 , Marc Naven  3 , Nasim Mavaddat  3 , John R B Perry  4 , Eugene Gardner  5 , Douglas F Easton  3   6
Affiliations

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

Toqir K Mukhtar et al. J Med Genet. .

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.

Keywords: Genetics; Whole Exome Sequencing.

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Conflict of interest statement

Competing interests: DFE is listed as a creator of the BOADICEA model which has been licensed by Cambridge Enterprise, University of Cambridge. EG and JRBP hold shares in, and are employees of, Insmed.

Figures

Figure 1
Figure 1. Case-control and prospective cohort studies generated from UK Biobank data. Start of observation for the prospective study 6 months after the assessment date. Person 1: registry-reported breast cancer 2 years after the day of first assessment, and no prior cancers; contributes to both studies. Person 2: registry-reported prostate cancer prior to the first day of assessment; contributes to case-control study only. Person 3: self-reported ovarian cancer prior to the first day of assessment, and no registry-reported cancers; excluded from both studies. Person 4: registry-reported lung cancer 3 years after the day of first assessment; contributes to both studies. Person 5: registry-reported colon cancer 4 months after the start of observation; contributes to case-control study only. Person 6: no self-reported nor registry-reported cancers; contributes to both studies. RR: registry-reported cancer. SR: self-reported cancer.
Figure 2
Figure 2. Cumulative absolute pancreatic cancer risks for ATM protein-truncating and missense variant carriers, and in the general population, by age and sex. ATM, Ataxia-Telangiectasia Mutated; MSV, missense variant; PTV, protein-truncating variant.
See this image and copyright information in PMC

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