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Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

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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.

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Abbreviations

CRC:

Colorectal cancer

BER:

Base excision repair

MMR:

Mismatch repair

MSI:

Microsatellite instability

IHC:

Immunohistochemistry

FDR:

First-degree relatives

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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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Correspondence to Francesc Balaguer or Sergi Castellví-Bel.

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Giráldez, M.D., Balaguer, F., Caldés, T. et al. Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Familial Cancer 8, 525–531 (2009). https://doi.org/10.1007/s10689-009-9282-4

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  • DOI: https://doi.org/10.1007/s10689-009-9282-4

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