title: Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair.
abstract: Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Seguí
authors.affiliation: 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.
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Mina
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanz-Pamplona
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Tirso
authors.initials: T
authors.lastname: Pons
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bellido
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: López-Doriga
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdés-Mas
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guinó
authors.affiliation: Department of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: José Luís
authors.initials: JL
authors.lastname: Soto
authors.affiliation: Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.affiliation: Instituto de Biología y Genética Molecular, IBGM-UVA-CSIC, Valladolid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Durán
authors.affiliation: Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Centre and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rueda
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.affiliation: Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbín
authors.affiliation: Familial Cancer Unit, Department of Medical Oncology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Blay
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garré
authors.affiliation: Department of Oncology, Hospital General Yagüe, Burgos, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lastra
authors.affiliation: Unit of Genetic Counseling in Cancer, Elche University Hospital, Elche, Spain.
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: Sánchez-Heras
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pujana
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. Electronic address: lvalle@iconcologia.net.
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002675:Child, Preschool; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D040941:Heredity; D006801:Humans; D008297:Male; D008875:Middle Aged; D064251:Multifunctional Enzymes; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human
keywords: DNA Mismatch Repair; Genetic Risk Factor; Lynch Syndrome; Susceptibility