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Cancer genetics
Original research
Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank
  1. Eilidh Fummey1,
  2. Pau Navarro1,2,
  3. John-Paul Plazzer3,
  4. Ian M Frayling4,5,
  5. Sara Knott6,
  6. Albert Tenesa1,2
  1. 1 MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
  2. 2 The Roslin Institute, University of Edinburgh, Roslin, Midlothian, UK
  3. 3 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  4. 4 The Centre for Familial Intestinal Cancer, St Mark's the National Bowel Hospital and Academic Institute, London, UK
  5. 5 Institute of Cancer & Genetics, Cardiff University, Cardiff, UK
  6. 6 Institute of Ecology and Evolution, University of Edinburgh, Edinburgh, UK
  1. Correspondence to Dr Albert Tenesa; albert.tenesa{at}ed.ac.uk

Background

Lynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.

Methods 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).

Results Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in path_MMR carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in path_MMR carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic PMS2 variants in UKB.

Conclusion These results support offering incidentally identified carriers of any path_MMR surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in MLH1, MSH2 and MSH6 would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.

  • Genetic Predisposition to Disease
  • Human Genetics
  • Neoplasms
  • Whole Exome Sequencing
  • Germ-Line Mutation

Data availability statement

Data may be obtained from a third party and are not publicly available. Data used can be obtained through application to UK Biobank: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jmg-2023-109791

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    Data availability statement

    Data may be obtained from a third party and are not publicly available. Data used can be obtained through application to UK Biobank: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.

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    Footnotes

    • X @Doctor_IMF

    • Correction notice The article has been corrected since it was published online. Statements in the Acknowledgment section have been added for clarity. To comply with UK Biobank's guidance, supplementary file 1 has been removed because all tables included values less than 5. The conclusions of the article have not been impacted by this change.

    • Contributors AT conceived the idea of the study. Analyses were planned by EF, PN, SK and AT. EF carried out the analysis. All authors contributed to the interpretation of analysis results. EF wrote the manuscript with input from all authors. AT acts as a guarantor.

    • Funding This work was funded under the awards from the Biotechnology and Biological Sciences Research Council (BB/S508032/1, BBS/E/D/10002070, BBS/E/D/30002275, BBS/E/RL/230001A), Health Data Research UK (HDR-9004) and the Medical Research Council (MC_PC_U127561128, MC_PC_U127592696, MC_UU_00007/10, MR/P015514/1).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.