title: Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer.
abstract: Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Ruta
authors.initials: R
authors.lastname: Sahasrabudhe
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Lott
authors.affiliation: Grupo de Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia.
authors.forename: Mabel
authors.initials: M
authors.lastname: Bohorquez
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Ted
authors.initials: T
authors.lastname: Toal
authors.affiliation: Grupo de Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Estrada
authors.affiliation: Grupo de Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Suarez
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 15706 Santiago de Compostela, Galicia, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Brea-Fernández
authors.affiliation: Servicio de Anatomía Patológica, Hospital Clínico, Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Cameselle-Teijeiro
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social; Mexico City, Mexico.
authors.forename: Irma
authors.initials: I
authors.lastname: Ramos
authors.affiliation: Departamento de Patologia, La Unidad Medica Alta Especialidad Oncologia, Mexico City, Mexico.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Mantilla
authors.affiliation: Grupo de Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Prieto
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Corvalan
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Norero
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alvarez
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tapia
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Pilar
authors.initials: P
authors.lastname: Carvallo
authors.affiliation: Universidad de Antioquia and Instituto de Cancerología Las Américas, Medellin, Colombia.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Gonzalez
authors.affiliation: Universidad de Antioquia and Instituto de Cancerología Las Américas, Medellin, Colombia.
authors.forename: Alicia
authors.initials: A
authors.lastname: Cock-Rada
authors.affiliation: Instituto de Investigaciones Bioquímicas, Universidad de Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas y El Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno, Buenos Aires, Argentina.
authors.forename: Angela
authors.initials: A
authors.lastname: Solano
authors.affiliation: Laboratorio Genia, Montevideo, Uruguay.
authors.forename: Florencia
authors.initials: F
authors.lastname: Neffa
authors.affiliation: Laboratorio Genia, Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Della Valle
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Yau
authors.affiliation: Centro de Genética Médica Dr Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.affiliation: Department of Pathology, School of Medicine, University of California, Davis, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: Borowsky
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Yangcheng Cancer Hospital, Yangcheng, Shanxi, PR China.
authors.forename: Li-Ji
authors.initials: LJ
authors.lastname: He
authors.affiliation: Shanxi Cancer Hospital, Taiyuan, Shanxi, PR China.
authors.forename: Xiao-You
authors.initials: XY
authors.lastname: Han
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.affiliation: Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, Instituto Mexicano del Seguro Social; Mexico City, Mexico.
authors.forename: Javier
authors.initials: J
authors.lastname: Torres
authors.affiliation: Grupo de Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Colombia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Echeverry
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 15706 Santiago de Compostela, Galicia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California; Fundación de Genómica y Genética Molecular, Colombia. Electronic address: lgcarvajal@ucdavis.edu.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D059767:Recombinational DNA Repair / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C448305:RAD51C protein, human; D025521:Tumor Suppressor Proteins
keywords: Interaction; Stomach; Tumor; WES