title: The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer.
abstract: Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC.
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Esteban-Jurado
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Sebastià
authors.initials: S
authors.lastname: Franch-Expósito
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ocaña
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Sabela
authors.initials: S
authors.lastname: Carballal
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: López-Cerón
authors.affiliation: Department of Pathology, Hospital Clinic, Barcelona, Spain.
authors.forename: Miriam
authors.identifier: 0000-0003-3063-0110
authors.initials: M
authors.lastname: Cuatrecasas
authors.affiliation: Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vila-Casadesús
authors.affiliation: Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Centre Nacional d'Anàlisi Genòmica (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Serra
authors.affiliation: Centre Nacional d'Anàlisi Genòmica (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Beltran
authors.affiliation: Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Brea-Fernández
authors.affiliation: Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Gastroenterology Department, Hospital Donostia-Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Country University (UPV/EHU), San Sebastián, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garre
authors.affiliation: Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.affiliation: Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Biomédica Ourense, Pontevedra y Vigo, Ourense, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Cubiella
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.affiliation: Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D059472:Exome; D005199:Fanconi Anemia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D052239:Fanconi Anemia Complementation Group E Protein / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010375:Pedigree; D013030:Spain
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499907:FANCE protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052239:Fanconi Anemia Complementation Group E Protein; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human