title: Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.
abstract: Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre Nordlab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Tuomo
authors.identifier: http://orcid.org/0000-0003-3284-4403
authors.initials: T
authors.lastname: Mantere
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre Nordlab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tervasmäki
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Nurmi
authors.affiliation: Laboratory of Genetics, Northern Finland Laboratory Centre NordLab Oulu, Oulu, Finland.|Cancer Genetic Unit, Service and Central Laboratory of Haematology, CHUV, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.affiliation: Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Saila
authors.initials: S
authors.lastname: Kauppila
authors.affiliation: Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Tang
authors.affiliation: Medical Biochemistry and Genetics Institute of Biomedicine, University of Turku, Turku, Finland.|Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors.forename: Johanna
authors.identifier: http://orcid.org/0000-0002-1863-0305
authors.initials: J
authors.lastname: Schleutker
authors.affiliation: BioMediTech and FimLab Laboratories, University of Tampere, Tampere, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Medical Informatics and Statistics Research Group, University of Oulu, Oulu, Finland.
authors.forename: Pentti
authors.identifier: http://orcid.org/0000-0003-0591-586X
authors.initials: P
authors.lastname: Nieminen
authors.affiliation: Laboratory of Genetics, Northern Finland Laboratory Centre NordLab Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Hanhisalo
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Lehto
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Suvanto
authors.affiliation: Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Grip
authors.affiliation: Department of Oncology, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Arja
authors.initials: A
authors.lastname: Jukkola-Vuorinen
authors.affiliation: Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Tengström
authors.affiliation: Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Auvinen
authors.affiliation: Department of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Anders
authors.identifier: http://orcid.org/0000-0002-1358-0695
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Department of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Department of Oncology, Helsinki University Hospital, Helsinki, Finland.|Department of Oncology, University of Örebro, Örebro, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre Nordlab Oulu, University of Oulu, Oulu, Finland. robert.winqvist@oulu.fi.
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Heli
authors.identifier: http://orcid.org/0000-0002-0916-2976
authors.initials: H
authors.lastname: Nevanlinna
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre Nordlab Oulu, University of Oulu, Oulu, Finland. katri.pylkas@oulu.fi.
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
mesh_terms: D000483:Alleles; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004252:DNA Mutational Analysis; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D015201:Meta-Analysis as Topic; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger; D057188:Workflow
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; C578814:TEX15 protein, human