| Title: | Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data |
| Journal: | Journal of Medical Genetics |
| Published: | 29 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39209703/ |
| DOI: | https://doi.org/10.1136/jmg-2024-110127 |
Publication 13065
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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.</p>
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%).</p>
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).</p>
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.</p>
16 Keywords
- Aged
- Ataxia Telangiectasia Mutated Proteins
- Biological Specimen Banks
- Case-Control Studies
- Checkpoint Kinase 2
- Exome Sequencing
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Mutation, Missense
- Neoplasms
- Retrospective Studies
- UK Biobank
- United Kingdom
9 Authors
- Toqir K Mukhtar
- Naomi Wilcox
- Joe Dennis
- Xin Yang
- Marc Naven
- Nasim Mavaddat
- John R B Perry
- Eugene Gardner
- Douglas F Easton
1 Application
| Application ID | Title |
|---|---|
| 28126 | Validating risk prediction models for common hormonal cancers |
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