SO08: Identification of novel causal genes of hereditary colorectal cancer

Nuria Segui1, Fernando Bellido1, Matilde Navarro1, Leonardo B. Mina2, Tirso Pons3, Marta Pineda1, Rafael Valdés-Mas4, Nicole Köger5, Gemma Aiza1, Pilar Mur1, Rebeca Sanz-Pamplona6, Sami Belhadj1, Silvia Iglesias1, José Luís Soto7, Miguel Urioste8, Trinidad Caldés9, Milagros Balbín10, Pilar Blay11, Daniel Rueda12, Mercedes Durán13, Alfonso Valencia3, Ignacio Blanco1, Joan Brunet14, Victor Moreno15, Guido Plotz5, Jordi Surrallés2, Xose S. Puente4, Conxi Lázaro1, Gabriel Capellá1, Laura Valle1.

1 –  Hereditary Cancer Program. Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. 2 –  Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, and Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain. 3 – Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 4 – Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain. 5 – Biomedical Research Laboratory, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany. 6 – Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain. 7 – Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain. 8 – Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Centre and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain. 9 – Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain. 10 – Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain. 11 – Familial Cancer Unit, Department of Medical Oncology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain. 12 – Laboratory of Molecular Biology, 12 de Octubre University Hospital, Madrid, Spain. 13 – Instituto de Biología y Genética Molecular, IBGM-UVA-CSIC, Valladolid, Spain. 14 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain. 15 – Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain.

Aim

Inherited factors account for over 20% of all colorectal cancers (CRC), but less than 6% can be explained by rare high-penetrance mutations in known genes. We aimed at identifying novel hereditary cancer genes by performing whole-exome sequencing (WES) in individual hereditary CRC families.

Method

WES was performed in 3 Amsterdam-positive families (3 CRC-affected members were studied per family). Validation studies in familial cancer series and in silico and in vitro analyses were carried out.

Results

One family harbored two mutations in the MUTYH gene –known polyposis (recesive) gene-, one recurrent in the European population and the other novel, for which functional studies demonstrated its deleterious nature. The family showed an atypical phenotype for MUYTH, characterized by the absence of polyps, apparent autosomal dominant inheritance, and presence of a mismatch repair-deficient tumour. The study of the second family allowed us to identify a novel hereditary CRC gene, FAN1. Functionally relevant mutations were identified in almost 3% of Amsterdam-positive families. The third family carried mutations in two candidate genes: a splice-site mutation in a tumour suppressor gene, and a missense mutation in a previously proposed cancer-predisposing gene.

Conclusion

In summary, the analysis of exomes in individual high-risk families allowed us to identify two novel genes for hereditary CRC, as well as mutations in previously known or previously proposed CRC-predisposing genes.

Top