title: Germline PARP4 mutations in patients with primary thyroid and breast cancers.
abstract: Germline mutations in the PTEN gene, which cause Cowden syndrome, are known to be one of the genetic factors for primary thyroid and breast cancers; however, PTEN mutations are found in only a small subset of research participants with non-syndrome breast and thyroid cancers. In this study, we aimed to identify germline variants that may be related to genetic risk of primary thyroid and breast cancers. Genomic DNAs extracted from peripheral blood of 14 PTEN WT female research participants with primary thyroid and breast cancers were analyzed by whole-exome sequencing. Gene-based case-control association analysis using the information of 406 Europeans obtained from the 1000 Genomes Project database identified 34 genes possibly associated with the phenotype with P < 1.0 × 10(-3). Among them, rare variants in the PARP4 gene were detected at significant high frequency (odds ratio = 5.2; P = 1.0 × 10(-5)). The variants, G496V and T1170I, were found in six of the 14 study participants (43%) while their frequencies were only 0.5% in controls. Functional analysis using HCC1143 cell line showed that knockdown of PARP4 with siRNA significantly enhanced the cell proliferation, compared with the cells transfected with siControl (P = 0.02). Kaplan-Meier analysis using Gene Expression Omnibus (GEO), European Genome-phenome Archive (EGA) and The Cancer Genome Atlas (TCGA) datasets showed poor relapse-free survival (P < 0.001, Hazard ratio 1.27) and overall survival (P = 0.006, Hazard ratio 1.41) in a PARP4 low-expression group, suggesting that PARP4 may function as a tumor suppressor. In conclusion, we identified PARP4 as a possible susceptibility gene of primary thyroid and breast cancer.
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Poh Yin
authors.initials: PY
authors.lastname: Yew
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Taigo
authors.initials: T
authors.lastname: Kato
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Kai Lee
authors.initials: KL
authors.lastname: Yap
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nielsen
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA rgrogan@surgery.bsd.uchicago.edu.
authors.forename: Raymon H
authors.initials: RH
authors.lastname: Grogan
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; C118687:PARP4 protein, human
keywords: PARP4; breast; cancer; germline mutation; thyroid