Skip to main content

Advertisement

SpringerLink
Log in

Frequency of the common germline MUTYH mutations p.G396D and p.Y179C in patients diagnosed with colorectal cancer in Southern Brazil

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. 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

    Article  PubMed  CAS  Google Scholar 

  2. David SS, O'Shea VL, Kundu S (2007) Base-excision repair of oxidative DNA damage. Nature 447(7147):941–950

    Article  PubMed  CAS  Google Scholar 

  3. Slupska MM, Baikalov C, Luther WM et al (1996) 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 178:3885–3892

    PubMed  CAS  Google Scholar 

  4. Vogt S, Jones N, Christian D et al (2009) Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137:1976–1985

    Article  PubMed  CAS  Google Scholar 

  5. Nielsen M, Franken PF, Reinards TH et al (2005) Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 42:e54. doi:10.1136/jmg.2005.033217

    Article  PubMed  CAS  Google Scholar 

  6. Wasielewski M, Out AA, Vermeulen J et al (2010) Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. Breast Cancer Res Treat. doi:10.1007/s10549-010-0801-7 [epub Feb 27]

    Google Scholar 

  7. Cheadle JP, Sampson JR (2007) MUTYH-associated polyposis—from defect in base excision repair to clinical genetic testing. DNA Repair (Amst) 6:274–279. doi:10.1016/j.dnarep.2006.11.001

    Article  CAS  Google Scholar 

  8. Lipton L, Tomlinson I (2006) The genetics of FAP and FAP-like syndromes. Fam Cancer 5:221–226. doi:10.1007/s10689-005-5673-3

    Article  PubMed  CAS  Google Scholar 

  9. Eliason K, Hendrickson BC, Judkins T et al (2005) 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 42:95–96. doi:10.1136/jmg.2004.025973

    Article  PubMed  CAS  Google Scholar 

  10. Grunhage F, Jungck M, Lamberti C et al (2008) Contribution of common monoallelic MUTYH gene variants in German patients with familial colorectal cancer. Cancer Biomark 4:55–61

    PubMed  Google Scholar 

  11. Kambara T, Whitehall VL, Spring KJ et al (2004) Role of inherited defects of MYH in the development of sporadic colorectal cancer. Genes Chromosomes Cancer 40:1–9. doi:10.1002/gcc.20011

    Article  PubMed  CAS  Google Scholar 

  12. Peterlongo P, Mitra N, Sanchez de Abajo A et al (2006) Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis 27:2243–2249. doi:10.1093/carcin/bgl093

    Article  PubMed  CAS  Google Scholar 

  13. Stormorken AT, Hoff G, Norstein J et al (2006) MUTYH mutations do not cause HNPCC or late onset colorectal cancer. Hered Cancer Clin Pract 2:90–93

    Article  Google Scholar 

  14. 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. doi:10.1089/gte.2005.9.147

    Article  PubMed  CAS  Google Scholar 

  15. Jones S, Emmerson P, Maynard J et al (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C→T:A mutations. Hum Mol Genet 11(23):296–2967

    Article  Google Scholar 

  16. Sieber OM, Lipton L, Crabtree M et al (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348(9):791–799

    Article  PubMed  Google Scholar 

  17. Nielsen M, Joerink-van de Beld MC, Jones N et al (2009) Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology 136:471–476. doi:10.1053/j.gastro.2008.10.056

    Article  PubMed  CAS  Google Scholar 

  18. Croitoru ME, Cleary SP, Di Nicola N et al (2004) Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 96:1631–1634

    Article  PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Balaguer F, Castellvi-Bel S, Castells A et al (2007) Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol 5:379–387

    Article  PubMed  CAS  Google Scholar 

  22. Dunlop MG, Farrington SM (2010) MUTYH-associated polyposis and colorectal cancer. Crit Rev Oncol Hematol 18:599–610

    Google Scholar 

  23. Chmiel NH, Livingston AL, David SS (2003) 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 327:431–443

    Article  PubMed  CAS  Google Scholar 

  24. Fromme JC, Banerjee A, Huang SJ, Verdine GL (2004) Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature 427:652–656

    Article  PubMed  CAS  Google Scholar 

  25. D'Agostino VG, Minoprio A, Torreri P et al (2010) Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst) 9:700–707

    Article  Google Scholar 

  26. Sampson JR, Jones S, Dolwani S, Cheadle JP (2005) MUTYH (MYH) and colorectal cancer. Biochem Soc Trans 33:679–683

    Article  PubMed  CAS  Google Scholar 

  27. 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. Hereditary Cancer Clin Pract 3:65–70

    Article  CAS  Google Scholar 

  28. Salzano FM, Bortolini MC (2002) Evolution and genetics of Latin American populations. Cambridge University Press, Cambridge

    Google Scholar 

  29. Aceto G, Curia MC, Veschi S et al (2005) Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum Mutat 26(4):394

    Article  PubMed  Google Scholar 

  30. 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

    Article  PubMed  CAS  Google Scholar 

  31. Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E (2010) MUTYH-associated polyposis—variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 78:353–363

    Article  PubMed  CAS  Google Scholar 

  32. Kim IJ, Ku JL, Kang HC et al (2004) Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients. Hum Genet 115:498–503

    Article  PubMed  CAS  Google Scholar 

  33. Ali M, Kim H, Cleary S et al (2008) Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology 135:499–507

    Article  PubMed  CAS  Google Scholar 

  34. Parker AR, Sieber OM, Shi C et al (2005) Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair. Carcinogenesis 26:2010–2018

    Article  PubMed  CAS  Google Scholar 

  35. 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(5):680–684

    Article  PubMed  CAS  Google Scholar 

  36. Jo WS, Bandipalliam P, Shannon KM et al (2005) Correlation of polyp number and family history of colon cancer with germline MYH mutations. Clin Gastroenterol Hepatol 3(10):1022–1028

    Article  PubMed  CAS  Google Scholar 

  37. Kairupan CF, Meldrum CM, Crooks R, Milward EA, Spiegelman AD, Burgess B, Groombridge C, Kirk J, Tucker K, Ward R, Williams R, Scott RJ (2011) Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. Int J Cancer (in press)

Download references

Acknowledgments

We are indebted to the patients and their family members who agreed to participate in this study and to Fundação de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPe-HCPA) who provided the financial support. We also thank Drs. Hector Yuri Wanderley, Daniel Damin, Bernardo Garicochea, Cristina Netto, and the coloproctology team at Hospital de Clínicas de Porto Alegre for the patient referrals. We are indebted to Stefan Aretz (Institute of Human Genetics, Bonn, Germany) for the sequencing protocols. We also thank Dr. Rogério Margis (Departamento de Genética, Universidade Federal do Rio Grande do Sul) for guidance in establishing the real-time PCR protocols. CEP, SLC, and PAP received grants from CNPq, and PKS received a grant from CAPES.

Author information

Authors and Affiliations

  1. Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil

    Carlos E. Pitroski, Silvia Liliana Cossio, Patrícia Koehler-Santos & Patricia Ashton-Prolla

  2. Programa de Pós Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Carlos E. Pitroski, Patrícia Koehler-Santos, Marcia Graudenz & Patricia Ashton-Prolla

  3. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, Brazil

    Silvia Liliana Cossio & Patricia Ashton-Prolla

  4. Departamento de Patologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Marcia Graudenz & João Carlos Prolla

  5. Programa de Pós Graduação em Medicina: Ciências Gastroenterológicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Carlos E. Pitroski, Silvia Liliana Cossio, Patrícia Koehler-Santos, Marcia Graudenz, João Carlos Prolla & Patricia Ashton-Prolla

  6. Departamento de Genética, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Patricia Ashton-Prolla

  7. Programa de Pós Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Patricia Ashton-Prolla

  8. Departamento de Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS) and Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, CEP: 90035–903, Porto Alegre, RS, Brazil

    Patricia Ashton-Prolla

Authors
  1. Carlos E. Pitroski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Liliana Cossio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrícia Koehler-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcia Graudenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. João Carlos Prolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia Ashton-Prolla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia Ashton-Prolla.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pitroski, C.E., Cossio, S.L., Koehler-Santos, P. et al. Frequency of the common germline MUTYH mutations p.G396D and p.Y179C in patients diagnosed with colorectal cancer in Southern Brazil. Int J Colorectal Dis 26, 841–846 (2011). https://doi.org/10.1007/s00384-011-1172-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-011-1172-1

Keywords

Search

Navigation