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Gastroenterology. 2015 Sep;149(3):563-6. doi: 10.1053/j.gastro.2015.05.056. Epub 2015 Jun 5.

Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair.

Author information

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
Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology, IDIBELL and CIBERESP, Hospitalet de Llobregat, Spain.
4
Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
5
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
6
Department of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.
7
Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
8
Laboratorio de Oncología Molecular, Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.
9
Instituto de Biología y Genética Molecular, IBGM-UVA-CSIC, Valladolid, Spain.
10
Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Centre and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain.
11
Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain.
12
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.
13
Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
14
Familial Cancer Unit, Department of Medical Oncology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
15
Department of Oncology, Hospital General Yagüe, Burgos, Spain.
16
Unit of Genetic Counseling in Cancer, Elche University Hospital, Elche, Spain.
17
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.
18
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
19
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. Electronic address: lvalle@iconcologia.net.

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.

KEYWORDS:

DNA Mismatch Repair; Genetic Risk Factor; Lynch Syndrome; Susceptibility

PMID:
26052075
DOI:
10.1053/j.gastro.2015.05.056
[Indexed for MEDLINE]
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