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Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene

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Abstract

The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understandin g the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone. Of the 10 carriers of both gene mutations, 8 were diagnosed with colorectal cancer. Using a weighted cohort analysis, we estimated that risk of colorectal cancer for carriers of both a MUTYH and a MMR gene mutation was substantially higher than that for carriers of a MUTYH mutation alone [hazard ratio (HR) 21.5, 95 % confidence interval (CI) 9.19–50.1; p < 0.001], but not different from that for carriers of a MMR gene mutation alone (HR 1.94, 95 % CI 0.63–5.99; p = 0.25). Within the limited power of this study, there was no evidence that a monoallelic MUTYH gene mutation confers additional risk of colorectal cancer for carriers of a MMR gene mutation alone. Our finding suggests MUTYH mutation testing in MMR gene mutation carriers is not clinically informative.

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Acknowledgments

The authors thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project.

Funding

This work was supported by Grant UM1 CA167551 from the National Cancer Institute, National Institutes of Health (NIH) and through cooperative agreements with members of the Colon Cancer Family Registry (CFR) and Principal Investigators. Collaborating centers include Australasian Colorectal Cancer Family Registry (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), Stanford Consortium Colorectal Cancer Family Registry (U01/U24 CA074799), and University of Hawaii Colorectal Cancer Family Registry (U01/U24 CA074806). A.K.W. is an Australian National Health and Medical Research Council (NHMRC) Early Career Fellow. M.A.J. is an NHMRC Senior Research Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. D.D.B. is a University of Melbourne Research at Melbourne Accelerator Program (R@MAP) Senior Research Fellow.

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Authors and Affiliations

  1. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Level 3, 207 Bouverie Street, Parkville, VIC, 3010, Australia

    Aung Ko Win, Jeanette C. Reece, Daniel D. Buchanan, James G. Dowty, Robert J. MacInnis, John L. Hopper & Mark A. Jenkins

  2. Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

    Daniel D. Buchanan & Mark Clendenning

  3. Department of Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia

    Joanne P. Young

  4. SAHMRI Colorectal Node, Basil Hetzel Institute for Translational Research, Woodville, SA, Australia

    Joanne P. Young

  5. School of Medicine, University of Adelaide, Adelaide, SA, Australia

    Joanne P. Young

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

    Sean P. Cleary, Hyeja Kim & Steven Gallinger

  7. Cancer Care Ontario, Toronto, ON, Canada

    Michelle Cotterchio

  8. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia

    Robert J. MacInnis

  9. Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, NSW, Australia

    Katherine M. Tucker

  10. Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia

    Ingrid M. Winship

  11. Department of Medicine, The University of Melbourne, Parkville, VIC, Australia

    Ingrid M. Winship & Finlay A. Macrae

  12. Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia

    Finlay A. Macrae

  13. University of Hawaii Cancer Center, Honolulu, HI, USA

    Terrilea Burnett & Loïc Le Marchand

  14. Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Graham Casey

  15. Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA

    Robert W. Haile

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

    Polly A. Newcomb

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

    Polly A. Newcomb

  18. Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Stephen N. Thibodeau

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

    Noralane M. Lindor

  20. Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea

    John L. Hopper

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  1. Aung Ko Win
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  2. Jeanette C. Reece
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  6. Sean P. Cleary
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  9. James G. Dowty
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  11. Katherine M. Tucker
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  13. Finlay A. Macrae
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  14. Terrilea Burnett
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  15. Loïc Le Marchand
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  16. Graham Casey
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  17. Robert W. Haile
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  19. Stephen N. Thibodeau
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  20. Noralane M. Lindor
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  21. John L. Hopper
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  22. Steven Gallinger
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  23. Mark A. Jenkins
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Corresponding author

Correspondence to Aung Ko Win.

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The authors have no conflict of interest to declare with respect to this manuscript.

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Disclaimer: 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 CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR.

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Win, A.K., Reece, J.C., Buchanan, D.D. et al. Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene. Familial Cancer 14, 575–583 (2015). https://doi.org/10.1007/s10689-015-9824-x

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