title: Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene.
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.
authors.affiliation: 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. awin@unimelb.edu.au.
authors.forename: Aung Ko
authors.identifier: http://orcid.org/0000-0002-2794-5261
authors.initials: AK
authors.lastname: Win
authors.affiliation: 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.
authors.forename: Jeanette C
authors.initials: JC
authors.lastname: Reece
authors.affiliation: 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.|Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Department of Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia.|SAHMRI Colorectal Node, Basil Hetzel Institute for Translational Research, Woodville, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cleary
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Hyeja
authors.initials: H
authors.lastname: Kim
authors.affiliation: Cancer Care Ontario, Toronto, ON, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.affiliation: 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.
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.affiliation: 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.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: MacInnis
authors.affiliation: Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Tucker
authors.affiliation: Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.|Department of Medicine, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Winship
authors.affiliation: Department of Medicine, The University of Melbourne, Parkville, VIC, Australia.|Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.affiliation: University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Terrilea
authors.initials: T
authors.lastname: Burnett
authors.affiliation: University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: School of Public Health, University of Washington, Seattle, WA, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: 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.|Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: 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.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: Colorectal cancer; Lynch syndrome; MUTYH; Mismatch repair