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.
MUTYHMismatch repair Colorectal cancer Lynch syndrome
This is a preview of subscription content, log in to check access.
The authors thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project.
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.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to declare with respect to this manuscript.
Win AK, Young JP, Lindor NM et al (2012) Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30(9):958–964PubMedCentralCrossRefPubMedGoogle Scholar
Win AK, Cleary SP, Dowty JG et al (2011) Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer 129(9):2256–2262PubMedCentralCrossRefPubMedGoogle Scholar
Win AK, Dowty JG, Cleary SP et al (2014) Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146(5):1208–1211PubMedCentralCrossRefPubMedGoogle Scholar
Jenkins MA, Croitoru ME, Monga N et al (2006) Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomarkers Prev 15(2):312–314CrossRefPubMedGoogle Scholar
Cleary SP, Cotterchio M, Jenkins MA et al (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case–control study. Gastroenterology 136(4):1251–1260PubMedCentralCrossRefPubMedGoogle Scholar
Kruger S, Engel C, Bier A et al (2007) The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1. Cancer Lett 252(1):55–64CrossRefPubMedGoogle Scholar
Maillet P, Chappuis PO, Vaudan G et al (2000) A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. Int J Cancer 88(6):928–931CrossRefPubMedGoogle Scholar
Moisio AL, Sistonen P, Mecklin JP, Jarvinen H, Peltomaki P (1998) Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer. Gastroenterology 115(6):1387–1394CrossRefPubMedGoogle Scholar
Campbell PT, Edwards L, McLaughlin JR, Green J, Younghusband HB, Woods MO (2007) Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland. Clin Cancer Res 13(13):3783–3788CrossRefPubMedGoogle Scholar
Chen J, Pande M, Huang YJ et al (2013) Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients. Carcinogenesis 34(2):299–306PubMedCentralCrossRefPubMedGoogle Scholar
Felix R, Bodmer W, Fearnhead NS, van der Merwe L, Goldberg P, Ramesar RS (2006) GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation. Mutat Res 602(1–2):175–181CrossRefPubMedGoogle Scholar
Frazier ML, O’Donnell FT, Kong S et al (2001) Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. Cancer Res 61(4):1269–1271PubMedGoogle Scholar
Kong S, Amos CI, Luthra R, Lynch PM, Levin B, Frazier ML (2000) Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res 60(2):249–252PubMedGoogle Scholar
Win AK, Hopper JL, Buchanan DD et al (2013) Are the common genetic variants known to be associated with colorectal cancer risk in the general population also associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers? Eur J Cancer 49(7):1578–1587PubMedCentralCrossRefPubMedGoogle Scholar
Gu Y, Parker A, Wilson TM, Bai H, Chang D-Y, Lu AL (2002) Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. J Biol Chem 277(13):11135–11142CrossRefPubMedGoogle Scholar
Giráldez M, Balaguer F, Caldés T et al (2009) Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 8(4):525–531CrossRefPubMedGoogle Scholar
Niessen R, Sijmons R, Ou J et al (2006) MUTYH and the mismatch repair system: partners in crime? Hum Genet 119(1):206–211CrossRefPubMedGoogle Scholar
Steinke V, Rahner N, Morak M et al (2008) No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. Eur J Hum Genet 16(5):587–592CrossRefPubMedGoogle Scholar
Stormorken A, Heintz K-M, Andresen PA, Hovig E, Møller P (2006) MUTYH mutations do not cause HNPCC or late onset familial colorectal cancer. Hered Cancer Clin Pract 4(2):90–93PubMedCentralCrossRefPubMedGoogle Scholar
van Puijenbroek M, Nielsen M, Reinards T et al (2007) The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Fam Cancer 6(1):43–51CrossRefPubMedGoogle Scholar
Ashton KA, Meldrum CJ, McPhillips ML, Kairupan CF, Scott RJ (2005) Frequency of the common MYH mutations (G382D and Y165C) in MMR mutation positive and negative HNPCC patients. Hered Cancer Clin Pract 3(2):65–70PubMedCentralCrossRefPubMedGoogle Scholar
Gorgens H, Kruger S, Kuhlisch E et al (2006) Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH. J Mol Diagn 8(2):178–182PubMedCentralCrossRefPubMedGoogle Scholar
Newcomb PA, Baron J, Cotterchio M et al (2007) Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 16(11):2331–2343CrossRefPubMedGoogle Scholar
Fritz A, Percy C, Jack A et al (eds) (2000) International classification of diseases for oncology (ICD-O), 3rd edn. World Health Organization, GenevaGoogle Scholar
Southey MC, Jenkins MA, Mead L et al (2005) Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 23(27):6524–6532CrossRefPubMedGoogle Scholar
Antoniou AC, Goldgar DE, Andrieu N et al (2005) A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol 29(1):1–11CrossRefPubMedGoogle Scholar
Jenkins MA, Baglietto L, Dowty JG et al (2006) Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol 4(4):489–498CrossRefPubMedGoogle Scholar
Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds) (2002) Cancer incidence in five continents, vol 8. International Agency for Research on Cancer, LyonGoogle Scholar
Rogers WH (1993) Regression standard errors in clustered samples. Stata Tech Bull 3(13):19–23Google Scholar