title: Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer.
abstract: The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of "bonafide" breast cancer susceptibility genes.
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: 0000-0001-7116-6364
authors: A
authors: Rump
authors: MGZ-Medical Genetics Center, Munich, Germany.
authors: Anna
authors: A
authors: Benet-Pages
authors: Clinic for Dermatology Venerology and Allergology, Göttingen, Germany.
authors: Steffen
authors: S
authors: Schubert
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.|Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Jan Dominik
authors: JD
authors: Kuhlmann
authors: Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Vilnius, Lithuania.|State Research Institute Innovative Medicine Center, Vilnius, Lithuania.
authors: Ramūnas
authors: R
authors: Janavičius
authors: Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors: Eva
authors: 0000-0002-0246-1471
authors: E
authors: Macháčková
authors: Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors: Lenka
authors: L
authors: Foretová
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Zdenek
authors: 0000-0003-2050-9667
authors: Z
authors: Kleibl
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Filip
authors: F
authors: Lhota
authors: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Petra
authors: P
authors: Zemankova
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Elitza
authors: E
authors: Betcheva-Krajcir
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Luisa
authors: L
authors: Mackenroth
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
authors: Karl
authors: 0000-0003-4181-2120
authors: K
authors: Hackmann
authors: Clinic for Dermatology Venerology and Allergology, Göttingen, Germany.
authors: Janin
authors: J
authors: Lehmann
authors: MGZ-Medical Genetics Center, Munich, Germany.
authors: Anke
authors: A
authors: Nissen
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Nataliya
authors: N
authors: DiDonato
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.|Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Romy
authors: R
authors: Opitz
authors: Cologne Center for Genomics, Cologne, Germany.
authors: Holger
authors: H
authors: Thiele
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.|Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Karin
authors: K
authors: Kast
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.|Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Pauline
authors: P
authors: Wimberger
authors: MGZ-Medical Genetics Center, Munich, Germany.
authors: Elke
authors: E
authors: Holinski-Feder
authors: Clinic for Dermatology Venerology and Allergology, Göttingen, Germany.|Clinic of Dermatology, Rostock, Germany.
authors: Steffen
authors: S
authors: Emmert
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
authors: Evelin
authors: 0000-0002-3377-1704
authors: E
authors: Schröck
authors: Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
authors: Barbara
authors: 0000-0002-8753-8238
authors: B
authors: Klink
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D051759:Xeroderma Pigmentosum Group D Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human