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Familial Cancer

, 8:525 | Cite as

Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

  • María Dolores Giráldez
  • Francesc Balaguer
  • Trinidad Caldés
  • Ana Sanchez-de-Abajo
  • Nuria Gómez-Fernández
  • Clara Ruiz-Ponte
  • Jenifer Muñoz
  • Pilar Garre
  • Victoria Gonzalo
  • Leticia Moreira
  • Teresa Ocaña
  • Joan Clofent
  • Angel Carracedo
  • Montserrat Andreu
  • Rodrigo Jover
  • Xavier Llor
  • Antoni Castells
  • Sergi Castellví-Bel
  • Gastrointestinal Oncology Group of the Spanish Gastroenterological Association
Article

Abstract

Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3′UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.

Keywords

Colorectal cancer Base excision repair MSH6 MUYH MUTYH Genetics 

Abbreviations

CRC

Colorectal cancer

BER

Base excision repair

MMR

Mismatch repair

MSI

Microsatellite instability

IHC

Immunohistochemistry

FDR

First-degree relatives

Notes

Acknowledgments

We are sincerely grateful to all patients participating in this study that were recruited in 25 Spanish hospitals as part of the EPICOLON project. We thank Ajay Goel for the critical review of this work. This work was supported by grants from the Fondo de Investigación Sanitaria (05/0071, 08/0024, 08/1276, 07/0359 and RD 06/0020/0021), Ministerio de Educación y Ciencia (SAF 07-64873), Asociación Española contra el Cáncer, Fundación Olga Torres (S. C.-B.), Fundación de Investigación Médica Mutua Madrileña (S. C.-B.), and Acción Transversal contra el Cáncer (Instituto de Salud Carlos III). F. B. received a research grant from Fundacion Caja Madrid. V. G. received a research grant from the Hospital Clínic, and S. C.-B. is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070). N. G.-F. received a Maria Barbeito’s Fellowship from Xunta de Galicia. CIBEREHD is funded by the Instituto de Salud Carlos III.

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • María Dolores Giráldez
    • 1
  • Francesc Balaguer
    • 1
  • Trinidad Caldés
    • 2
  • Ana Sanchez-de-Abajo
    • 2
  • Nuria Gómez-Fernández
    • 3
  • Clara Ruiz-Ponte
    • 3
  • Jenifer Muñoz
    • 1
  • Pilar Garre
    • 2
  • Victoria Gonzalo
    • 1
  • Leticia Moreira
    • 1
  • Teresa Ocaña
    • 1
  • Joan Clofent
    • 4
  • Angel Carracedo
    • 3
  • Montserrat Andreu
    • 5
  • Rodrigo Jover
    • 6
  • Xavier Llor
    • 7
  • Antoni Castells
    • 1
  • Sergi Castellví-Bel
    • 1
  • Gastrointestinal Oncology Group of the Spanish Gastroenterological Association
  1. 1.Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital ClínicCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)CataloniaSpain
  2. 2.Oncology Molecular LabHospital Clínico Universitario San CarlosMadridSpain
  3. 3.Galician Public Foundation of Genomic Medicine (FPGMX), CIBERER, Genomics Medicine Group, Hospital Clínico, Santiago de CompostelaUniversity of Santiago de CompostelaGaliciaSpain
  4. 4.Gastroenterology DepartmentHospital La FeValenciaSpain
  5. 5.Gastroenterology DepartmentHospital del MarCataloniaSpain
  6. 6.Unidad de GastroenterologíaHospital General Universitario de AlicanteAlicanteSpain
  7. 7.Section of Digestive Diseases and NutritionUniversity of Illinois at ChicagoChicagoUSA

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