Familial Cancer

, Volume 14, Issue 4, pp 575–583 | Cite as

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

  • Aung Ko Win
  • Jeanette C. Reece
  • Daniel D. Buchanan
  • Mark Clendenning
  • Joanne P. Young
  • Sean P. Cleary
  • Hyeja Kim
  • Michelle Cotterchio
  • James G. Dowty
  • Robert J. MacInnis
  • Katherine M. Tucker
  • Ingrid M. Winship
  • Finlay A. Macrae
  • Terrilea Burnett
  • Loïc Le Marchand
  • Graham Casey
  • Robert W. Haile
  • Polly A. Newcomb
  • Stephen N. Thibodeau
  • Noralane M. Lindor
  • John L. Hopper
  • Steven Gallinger
  • Mark A. Jenkins
Original Article

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.

Keywords

MUTYH Mismatch repair Colorectal cancer Lynch syndrome 

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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Aung Ko Win
    • 1
  • Jeanette C. Reece
    • 1
  • Daniel D. Buchanan
    • 1
    • 2
  • Mark Clendenning
    • 2
  • Joanne P. Young
    • 3
    • 4
    • 5
  • Sean P. Cleary
    • 6
  • Hyeja Kim
    • 6
  • Michelle Cotterchio
    • 7
  • James G. Dowty
    • 1
  • Robert J. MacInnis
    • 1
    • 8
  • Katherine M. Tucker
    • 9
  • Ingrid M. Winship
    • 10
    • 11
  • Finlay A. Macrae
    • 11
    • 12
  • Terrilea Burnett
    • 13
  • Loïc Le Marchand
    • 13
  • Graham Casey
    • 14
  • Robert W. Haile
    • 15
  • Polly A. Newcomb
    • 16
    • 17
  • Stephen N. Thibodeau
    • 18
  • Noralane M. Lindor
    • 19
  • John L. Hopper
    • 1
    • 20
  • Steven Gallinger
    • 6
  • Mark A. Jenkins
    • 1
  1. 1.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneParkvilleAustralia
  2. 2.Oncogenomics Group, Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneParkvilleAustralia
  3. 3.Department of OncologyThe Queen Elizabeth HospitalWoodvilleAustralia
  4. 4.SAHMRI Colorectal NodeBasil Hetzel Institute for Translational ResearchWoodvilleAustralia
  5. 5.School of MedicineUniversity of AdelaideAdelaideAustralia
  6. 6.Lunenfeld Tanenbaum Research Institute, Mount Sinai HospitalUniversity of TorontoTorontoCanada
  7. 7.Cancer Care OntarioTorontoCanada
  8. 8.Cancer Epidemiology CentreCancer Council VictoriaMelbourneAustralia
  9. 9.Hereditary Cancer ClinicPrince of Wales HospitalRandwickAustralia
  10. 10.Genetic Medicine and Family Cancer ClinicRoyal Melbourne HospitalParkvilleAustralia
  11. 11.Department of MedicineThe University of MelbourneParkvilleAustralia
  12. 12.Colorectal Medicine and GeneticsRoyal Melbourne HospitalParkvilleAustralia
  13. 13.University of Hawaii Cancer CenterHonoluluUSA
  14. 14.Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  15. 15.Division of Oncology, Department of MedicineStanford UniversityStanfordUSA
  16. 16.School of Public HealthUniversity of WashingtonSeattleUSA
  17. 17.Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  18. 18.Molecular Genetics Laboratory, Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  19. 19.Department of Health Science ResearchMayo Clinic ArizonaScottsdaleUSA
  20. 20.Department of Epidemiology and Institute of Health and Environment, School of Public HealthSeoul National UniversitySeoulKorea

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