title: Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer.
abstract: OBJECTIVE
  Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases.
  
  
  METHODS
  Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen.
  
  
  RESULTS
  Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1.
  
  
  CONCLUSIONS
  We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Clara
authors: C
authors: Esteban-Jurado
authors: Plataforma de Bioinformática, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors: Maria
authors: M
authors: Vila-Casadesús
authors: Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors: Pilar
authors: P
authors: Garre
authors: Plataforma de Bioinformática, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors: Juan José
authors: JJ
authors: Lozano
authors: 1] Centre Nacional d'Anàlisi Genòmica, Parc Científic de Barcelona, Barcelona, Spain [2] Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Anna
authors: A
authors: Pristoupilova
authors: Centre Nacional d'Anàlisi Genòmica, Parc Científic de Barcelona, Barcelona, Spain.
authors: Sergi
authors: S
authors: Beltran
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Jenifer
authors: J
authors: Muñoz
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Teresa
authors: T
authors: Ocaña
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Francesc
authors: F
authors: Balaguer
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Maria
authors: M
authors: López-Cerón
authors: Department of Pathology, Hospital Clinic, Barcelona, Spain.
authors: Miriam
authors: M
authors: Cuatrecasas
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Sebastià
authors: S
authors: Franch-Expósito
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Josep M
authors: JM
authors: Piqué
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Antoni
authors: A
authors: Castells
authors: Galician Public Foundation of Genomic Medicine, Centro de Investigación Biomédica en Red de Enfermedades Raras, Genomics Medicine Group, Hospital Clínico, University of Santiago de Compostela, Galicia, Spain.
authors: Angel
authors: A
authors: Carracedo
authors: Galician Public Foundation of Genomic Medicine, Centro de Investigación Biomédica en Red de Enfermedades Raras, Genomics Medicine Group, Hospital Clínico, University of Santiago de Compostela, Galicia, Spain.
authors: Clara
authors: C
authors: Ruiz-Ponte
authors: Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Spain.
authors: Anna
authors: A
authors: Abulí
authors: Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Spain.
authors: Xavier
authors: X
authors: Bessa
authors: Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Spain.
authors: Montserrat
authors: M
authors: Andreu
authors: Gastroenterology Department, Hospital Donostia - Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Country University (UPV/EHU), San Sebastián, Spain.
authors: Luis
authors: L
authors: Bujanda
authors: Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors: Trinidad
authors: T
authors: Caldés
authors: Servei de Gastroenterologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors: Sergi
authors: S
authors: Castellví-Bel
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D059472:Exome; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D010375:Pedigree; D015203:Reproducibility of Results