Rump, Andreas ORCID: 0000-0001-7116-6364, Benet-Pages, Anna, Schubert, Steffen, Kuhlmann, Jan Dominik, Janavicius, Ramunas, Machackova, Eva ORCID: 0000-0002-0246-1471, Foretov, Lenka, Kleibl, Zdenek ORCID: 0000-0003-2050-9667, Lhota, Filip, Zemankova, Petra, Betcheva-Krajcir, Elitza, Mackenroth, Luisa, Hackmann, Karl, Lehmann, Janin, Nissen, Anke, DiDonato, Nataliya, Opitz, Romy, Thiele, Holger, Kast, Karin, Wimberger, Pauline, Holinski-Feder, Elke, Emmert, Steffen, Schroeck, Evelin and Klink, Barbara (2016). Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer. PLoS Genet., 12 (8). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

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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

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rump, AndreasUNSPECIFIEDorcid.org/0000-0001-7116-6364UNSPECIFIED
Benet-Pages, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuhlmann, Jan DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janavicius, RamunasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Machackova, EvaUNSPECIFIEDorcid.org/0000-0002-0246-1471UNSPECIFIED
Foretov, LenkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleibl, ZdenekUNSPECIFIEDorcid.org/0000-0003-2050-9667UNSPECIFIED
Lhota, FilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zemankova, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Betcheva-Krajcir, ElitzaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackenroth, LuisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackmann, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehmann, JaninUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nissen, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DiDonato, NataliyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opitz, RomyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wimberger, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holinski-Feder, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Emmert, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeck, EvelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klink, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-267994
DOI: 10.1371/journal.pgen.1006248
Journal or Publication Title: PLoS Genet.
Volume: 12
Number: 8
Date: 2016
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1553-7404
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PIGMENTOSUM GROUP-D; XERODERMA-PIGMENTOSUM; DNA-REPAIR; XPD GENE; COCKAYNE-SYNDROME; TRICHOTHIODYSTROPHY; TRANSCRIPTION; INDIVIDUALS; ASSOCIATION; DEFICIENCYMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26799

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