Frequency of the Common Germline MUTYH Mutations P.G396D and P.Y179C in Patients Diagnosed with Colorectal Cancer in Southern Brazil

Overview

Journal Int J Colorectal Dis

Specialties Gastroenterology
General Surgery

Date 2011 Mar 23

PMID 21424714

Citations 12

Authors

Carlos E Pitroski

Silvia Liliana Cossio

Patricia Koehler-Santos

Marcia Graudenz

Joao Carlos Prolla

Patricia Ashton-Prolla

Affiliations

Soon will be listed here.

Abstract

Introduction: MUTYH-associated polyposis (MAP) is an autosomal recessive cancer predisposition syndrome associated with the development of colorectal tumors and colonic polyps at an early age. MAP syndrome is associated to germline biallelic mutations in the MUTYH gene which lead to deficient DNA repair through the base-excision repair system and accumulation of G:C→T:A transversions. Occurrence of such mutations in oncogenes and tumor suppressor genes drives colorectal carcinogenesis and is associated with the development of colonic polyps. Two common mutations, p.Y179C and p.G396D, are present in approximately 70-80% of MAP in European families with identified MUTYH germline mutations. The aim of this study was to assess the frequency of the germline MUTYH mutations p.Y179C and p.G396D in Brazilian patients with MAP and other hereditary colorectal cancer (CRC) phenotypes, as well as in sporadic CRC cases.

Materials And Methods: A total of 75 patients were included. Samples were screened for the MUTYH germline mutations p.Y179C and p.G396D by allelic discrimination assays using allele-specific TaqMan® probes. In all mutation-positive cases, results were confirmed by sequencing.

Results And Conclusions: Biallelic germline MUTYH mutations were identified in 4 of 60 (6.6%) patients with a phenotype of hereditary colorectal cancer. Germline MUTYH mutation screening should be considered in the differential diagnosis of hereditary colorectal syndromes, and not only in MAP, but also in familial adenomatous polyposis and Bethesda criteria-positive families. Additional mutation screening studies of the MUTYH gene in a larger number of Brazilian patients will be necessary to confirm these results and determine the validity and applicability of MUTYH mutation screening in our population.

Citing Articles

A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.

Esperon P, Neffa F, Pavicic W, Spirandelli F, Alvarez K, Mullins M Fam Cancer. 2024; 23(4):507-513.

PMID: 38687439 DOI: 10.1007/s10689-024-00382-3.

Screening for Mutations in Hereditary Cancer Susceptibility Genes in a Region with High Endogamy in Brazil.

Oliveira P, Correa P, Acosta A, Freitas J, Machado-Lopes T, Bomfim-Palma T Glob Med Genet. 2023; 10(4):376-381.

PMID: 38074417 PMC: 10709072. DOI: 10.1055/s-0043-1777449.

Cancer Risk Factors in Southern Brazil: Report of a Comprehensive, Matched Case-Control Study.

Giacomazzi J, Ziegelmann P, da Costa S, Bittar C, Obst F, Rosset C JCO Glob Oncol. 2023; 9:e2300006.

PMID: 38060977 PMC: 10723862. DOI: 10.1200/GO.23.00006.

The Unique Spectrum of Germline Mutations in Colombian Patients with Extracolonic Carcinomas.

Rodriguez-Rojas L, Candelo E, Pachajoa H, Garcia-Robledo J, Nastasi-Catanese J, Olave-Rodriguez J Appl Clin Genet. 2023; 16:53-62.

PMID: 37096204 PMC: 10122495. DOI: 10.2147/TACG.S370416.

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

Yu G, Pang Y, Merchant M, Kesserwan C, Gangalapudi V, Abdelmaksoud A Cancers (Basel). 2021; 13(23).

PMID: 34885201 PMC: 8657099. DOI: 10.3390/cancers13236092.

References

Kairupan C, Meldrum C, Crooks R, Milward E, Spigelman A, Burgess B . Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. Int J Cancer. 2005; 116(1):73-7. DOI: 10.1002/ijc.20983. View

Sieber O, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips R . Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003; 348(9):791-9. DOI: 10.1056/NEJMoa025283. View

Aceto G, Curia M, Veschi S, De Lellis L, Mammarella S, Catalano T . Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum Mutat. 2005; 26(4):394. DOI: 10.1002/humu.9370. View

Chmiel N, Livingston A, David S . Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes. J Mol Biol. 2003; 327(2):431-43. DOI: 10.1016/s0022-2836(03)00124-4. View

Cleary S, Cotterchio M, Jenkins M, Kim H, Bristow R, Green R . Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009; 136(4):1251-60. PMC: 2739726. DOI: 10.1053/j.gastro.2008.12.050. View

Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R . Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008; 135(2):499-507. PMC: 2761659. DOI: 10.1053/j.gastro.2008.04.035. View

Lipton L, Tomlinson I . The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006; 5(3):221-6. DOI: 10.1007/s10689-005-5673-3. View

Eliason K, Hendrickson B, Judkins T, Norton M, Leclair B, LYON E . The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005; 42(1):95-6. PMC: 1735918. DOI: 10.1136/jmg.2004.025973. View

DAgostino V, Minoprio A, Torreri P, Marinoni I, Bossa C, Petrucci T . Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst). 2010; 9(6):700-7. DOI: 10.1016/j.dnarep.2010.03.008. View

10.

Cheadle J, Sampson J . MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. DNA Repair (Amst). 2006; 6(3):274-9. DOI: 10.1016/j.dnarep.2006.11.001. View

11.

Stormorken A, Heintz K, Andresen P, Hovig E, Moller P . MUTYH Mutations Do Not Cause HNPCC or Late Onset Familial Colorectal Cancer. Hered Cancer Clin Pract. 2010; 4(2):90-3. PMC: 2837291. DOI: 10.1186/1897-4287-4-2-90. View

12.

Jones S, Emmerson P, Maynard J, Best J, Jordan S, Williams G . Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. Hum Mol Genet. 2002; 11(23):2961-7. DOI: 10.1093/hmg/11.23.2961. View

13.

Parker A, Sieber O, Shi C, Hua L, Takao M, Tomlinson I . Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair. Carcinogenesis. 2005; 26(11):2010-8. DOI: 10.1093/carcin/bgi166. View

14.

Nielsen M, Franken P, Reinards T, Weiss M, Wagner A, van der Klift H . Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet. 2005; 42(9):e54. PMC: 1736132. DOI: 10.1136/jmg.2005.033217. View

15.

Dunlop M, Farrington S . MUTYH-associated polyposis and colorectal cancer. Surg Oncol Clin N Am. 2009; 18(4):599-610. DOI: 10.1016/j.soc.2009.08.003. View

16.

Balaguer F, Castellvi-Bel S, Castells A, Andreu M, Munoz J, Gisbert J . Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol. 2007; 5(3):379-87. DOI: 10.1016/j.cgh.2006.12.025. View

17.

Slupska M, Baikalov C, Luther W, Chiang J, Wei Y, Miller J . Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J Bacteriol. 1996; 178(13):3885-92. PMC: 232650. DOI: 10.1128/jb.178.13.3885-3892.1996. View

18.

Wang L, Baudhuin L, Boardman L, Steenblock K, Petersen G, Halling K . MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004; 127(1):9-16. DOI: 10.1053/j.gastro.2004.03.070. View

19.

Fromme J, Banerjee A, Huang S, Verdine G . Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature. 2004; 427(6975):652-6. DOI: 10.1038/nature02306. View

20.

Grunhage F, Jungck M, Lamberti C, Schulte-Witte H, Plassmann D, Becker U . Contribution of common monoallelic MUTYH gene variants in German patients with familial colorectal cancer. Cancer Biomark. 2008; 4(2):55-61. DOI: 10.3233/cbm-2008-4201. View