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Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?

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Abstract

Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75–1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81–1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52–1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Therefore, despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we do not recommend that POEs be incorporated into the clinical guidelines or advice for such carriers.

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Funding

This work was supported by grant U01 CA167551 from the National Cancer Institute and through cooperative agreements with the following Colon Cancer Family Registry sites: Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800); Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783); Seattle Colorectal Cancer Family Registry (U01/U24 CA074794); University of Hawaii Colorectal Cancer Family Registry (U01/U24 CA074806); and USC Consortium Colorectal Cancer Family Registry U01/U24 CA074799). The targeted minority recruitment was supported by grant R01 CA104132. Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to the Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai‘i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C), and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California and HHSN261201000140C awarded to the Cancer Prevention Institute of California), the following US state cancer registries: AZ, CO, MN, NC and NH, and by the Victorian Cancer Registry, Australia and the Ontario Cancer Registry, Canada. A.K.W. is an NHMRC Career Development Fellow. M.A.J. is an NHMRC Senior Research Fellow. J.L.H. is an NHMRC Senior Principal Research Fellow. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR.

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Authors and Affiliations

  1. Centre for Epidemiology and Biostatistics, University of Melbourne, Parkville, VIC, Australia

    Shimelis Dejene Gemechu, Christine M. van Vliet, Aung Ko Win, John L. Hopper, Mark A. Jenkins & James G. Dowty

  2. Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia

    Aung Ko Win & Mark A. Jenkins

  3. Genetic Medicine, Royal Melbourne Hospital, Parkville, VIC, Australia

    Aung Ko Win

  4. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Jane C. Figueiredo

  5. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Jane C. Figueiredo

  6. University of Hawaii Cancer Center, Honolulu, Hawaii, USA

    Loic Le Marchand

  7. Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute, University of Toronto, Toronto, ON, Canada

    Steven Gallinger

  8. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Polly A. Newcomb

  9. School of Public Health, University of Washington, Seattle, WA, USA

    Polly A. Newcomb

  10. Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Noralane M. Lindor

Authors
  1. Shimelis Dejene Gemechu
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  2. Christine M. van Vliet
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  3. Aung Ko Win
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  4. Jane C. Figueiredo
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  6. Steven Gallinger
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  7. Polly A. Newcomb
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  8. John L. Hopper
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  9. Noralane M. Lindor
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  10. Mark A. Jenkins
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  11. James G. Dowty
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Corresponding author

Correspondence to James G. Dowty.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Melbourne Human Ethics Sub-Committee (ethics identification number 1339757) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gemechu, S.D., van Vliet, C.M., Win, A.K. et al. Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?. Familial Cancer 19, 215–222 (2020). https://doi.org/10.1007/s10689-020-00167-4

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  • DOI: https://doi.org/10.1007/s10689-020-00167-4

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