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Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype
  1. Nuria Seguí1,
  2. Matilde Navarro1,
  3. Marta Pineda1,
  4. Nicole Köger2,
  5. Fernando Bellido1,
  6. Sara González1,
  7. Olga Campos1,
  8. Silvia Iglesias1,
  9. Rafael Valdés-Mas3,
  10. Adriana López-Doriga4,
  11. Marta Gut5,
  12. Ignacio Blanco1,
  13. Conxi Lázaro1,
  14. Gabriel Capellá1,
  15. Xose S Puente3,
  16. Guido Plotz2,
  17. Laura Valle1
  1. 1 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain
  2. 2 Biomedical Research Laboratory, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
  3. 3 Department of Biochemistry and Molecular Biology, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain
  4. 4 Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain
  5. 5 Centro Nacional de Análisis Genómico, Fundació Parc Científic de Barcelona, Barcelona, Spain
  1. Correspondence to Dr Laura Valle, Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Av. Gran Via 199-203, Hospitalet de Llobregat 08908, Spain; lvalle{at} and to Dr Guido Plotz, Medizinische Klinik 1, Biomedizinisches Forschungslabor, Haus 11, Theodor-Stern-Kai 7, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; plotz{at}

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Ma et al 1 comprehensively assessed the association of previously reported genetic variants with colorectal cancer (CRC) risk. The meta-analyses revealed strong evidence for association with rare MUTYH variants, even when excluding cases with MUTYH-associated polyposis. An article by Nieuwenhuis et al 2 accurately defined the phenotypical features of MUTYH-associated polyposis. However, the study was performed on clinic-based series ascertained based on the inheritance model or the presence of polyps, which may miss additional phenotypes relevant to improve the disease characterisation and therefore, its genetic diagnosis. To illustrate this, we report a family with a clinical phenotype that resembled Lynch syndrome but was caused by MUTYH mutations.

To identify novel hereditary CRC genes, we studied an Amsterdam I family (hereditary non-polyposis CRC) with no mutations in the DNA mismatch repair (MMR) genes (figure 1, table 1). By exome sequencing performed on four cancer-affected (II.2, II.6, III.1 and III.6) and one cancer-free (III.5) family members, we identified a total of 11 unreported or rare heterozygous variants present in the cancer-affected individuals (see online supplementary table S1). One of them was MUTYH c.1147delC …

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  • LV and GP contributed equally to this work.

  • Contributors LV, GC, CL and GP conceived and designed the study and experiments. MN, MP, IB, OC, SG, CL, GC and LV collected data, performed genetic analyses, and provided samples and clinical data. NS, MG, FB, NK, OC, GP and LV performed the experiments and analysed the results. XSP, RV-M and AL-D analysed the next-gen sequencing data. LV and GP wrote the manuscript. All authors critically reviewed the manuscript and provided final approval.

  • Funding This work was funded by the Spanish Ministry of Economy and Competitiveness (State Secretariat for Research, Development and Innovation) (grants SAF2012-38885 and SAF2010-21165 to LV and XSP, Ramón y Cajal contract to LV, fellowship to FB, and RTICC networks RD12/0036/0031 and RD12/0036/0008); the Deutsche Krebshilfe (grant 110799 to GP); the Carlos III Health Institute (fellowship to NS); L'Oréal-UNESCO “For Women in Science”; the Scientific Foundation Asociación Española Contra el Cáncer; and the Government of Catalonia (grant 2009SGR290).

  • Ethics approval IDIBELL Ethics Committee.

  • Provenance and peer review Not commissioned; internally peer reviewed.