Abstract
Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (≥3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty-two of the 72 adenoma subjects (30.5 %) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra-intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR −5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer.
Similar content being viewed by others
Abbreviations
- AFAP:
-
Attenuated familial adenomatous polyposis
- CRC:
-
Colorectal cancer
- FAP:
-
Familial adenomatous polyposis
- MAP:
-
MUTYH-associated polyposis
References
Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited variants of MYH associated with somatic G:C → T: a mutations in colorectal tumors. Nat Genet 30:227–232
Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML, Hodgson SV, Aaltonen LA, Thomas HJ, Tomlinson IP (2003) Carcinogenesis in MYH-associated adenomatous polyps follows a distinct genetic pathway. Cancer Res 63:7595–7599
Farrington SM, Tenesa A, Barnetson R et al (2005) Germline Susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 77:112–119
Poulsen ML, Bisgaard ML (2008) MUTYH associated polyposis (MAP). Curr Genomics 9:420–435
Aretz S, Uhlhaas S, Goergens H et al (2006) MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 119(4):807–814
Grover S, Kastrinos F, Steyerberg EW et al (2012) Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA 308(5):485–492
Nieuwenhuis MH, Vogt S, Jones N et al (2012) Evidence for accelerated colorectal adenoma-carcinoma progression in MUTYH-associated polyposis? Gut 61(5):734–738
Nielsen M, de Miranda NF, van Puijenbroek M et al (2009) Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer 15(9):184–198
Goodenberger M, Lindor NM (2011) Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol 45:488–500
Chen H, Xu L, Qi Q et al (2008) A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese. BMC Cancer 8:269
Yanaru-Fujisawa R, Matsumoto T, Ushijima Y et al (2008) Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis. Clin Genet 73:545–553
Tao H, Shinmura K, Suzuki M et al (2008) Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population. Cancer Sci 99:355–360
Kim JC, Ka IH, Lee YM et al (2007) MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas. Virchows Arch 450:311–319
Gómez-Fernández N, Castellví-Bel S, Fernández-Rozadilla C et al (2009) Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations? BMC Med Genet 10:57
Gismondi V, Meta M, Bonelli L et al (2004) Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 109:680–684
Enholm S, Hienonen T, Suomalainen A et al (2003) Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Am J Pathol 163:827–832
Zhou XL, Djureinovic T, Werelius B et al (2005) Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer. Genet Test 9:147–151
Kanter-Smoler G, Björk J, Fritzell K et al (2006) Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization. Clin Gastroenterol Hepatol 4:499–506
Croitoru ME, Cleary SP, Berk T et al (2007) Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 95:499–506
Raetz AG, Xie Y, Kundu S et al (2012) Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. Carcinogenesis 33:2301–2309
Theodoratou E, Campbell H, Tenesa A et al (2010) A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer 103:1875–1884
Win AK, Hopper JL, Jenkins MA (2011) Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam Cancer 10:1–9
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 129:2256–2262
Lejbkowicz F, Cohen I, Barnett-Griness O et al (2012) Common MUTYH mutations and colorectal cancer risk in multiethnic populations. Fam Cancer 11:329–335
Rosner G, Rozen P, Bercovich D et al (2010) A protocol for genetic evaluation of patients with multiple colorectal adenomas and without evidence of APC gene mutation. Isr Med Assoc J 12:549–553
Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268
Raetz AG, Xie Y, Kundu S et al (2012) Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. Carcinogenesis 33(11):2301–2309
Picelli S, Zajac P, Zhou XL et al (2010) Common variants in human CRC genes as low-risk alleles. Eur J Cancer 46(6):1041–1048
Wang J, Lin M, Crenshaw A, Hutchinson A et al (2009) High-throughput single nucleotide polymorphism genotyping using nanofluidic Dynamic Arrays. BMC Genomics 10:561
Giráldez MD, Balaguer F, Caldés T et al (2009) Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 8(4):525–531
Out AA, Tops CM, Nielsen M et al (2010) Leiden open variation database of the MUTYH gene. Hum Mutat 31(11):1205–1215
Cleary SP, Cotterchio M, Jenkins MA et al (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 136:1251–1260
Jones N, Vogt S, Nielsen M, Christian D et al (2009) Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137:489–494
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 146:1208–1211
Laarabi FZ, Cherkaoui Jaouad I, Baert-Desurmont S et al (2012) The first mutations in the MYH gene reported in Moroccan colon cancer patients. Gene 496:55–58
Ali M, Kim H, Cleary S, Cupples C et al (2008) Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology 135:499–507
Lubbe SJ, Di Bernardo MC, Chandler IP et al (2009) Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 27:3975–3980
Knopperts AP, Nielsen M, Niessen RC et al (2013) Contribution of bi-allelic germline MUTYH mutations to early-onset and familial colorectal cancer and to low number of adenomatous polyps: case-series and literature review. Fam Cancer 12(1):43–50
Wang L, Baudhuin LM, Boardman LA et al (2004) MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 127:9–16
Niessen RC, Sijmons RH, Ou J et al (2006) MUTYH and the mismatch repair system: partners in crime? Hum Genet 119:206–211
van Puijenbroek M, Nielsen M, Reinards TH et al (2007) The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Fam Cancer 6:43–51
Giráldez MD, Balaguer F, Caldés T et al (2009) Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 8:525–531
Acknowledgments
We would like to express our sincere appreciation to the late Professor Paul Rozen. This study could not have been performed without his assistance and his profound intellectual contribution. Our thanks to the patients, department doctors and nurses for their cooperation, and especially to Serena Rosner, Sara Pel, Ziona Samuel and Sally Zimmerman for their assistance. This work was supported by the Sestopali Fund for Gastrointestinal Cancer Prevention and Katzman Family Foundation at Tel-Aviv University.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rosner, G., Bercovich, D., Daniel, Y.E. et al. Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews. Familial Cancer 14, 427–436 (2015). https://doi.org/10.1007/s10689-015-9799-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-015-9799-7