title: Rare ATAD5 missense variants in breast and ovarian cancer patients.
abstract: ATAD5/ELG1 is a protein crucially involved in replication and maintenance of genome stability. ATAD5 has recently been identified as a genomic risk locus for both breast and ovarian cancer through genome-wide association studies. We aimed to investigate the spectrum of coding ATAD5 germ-line mutations in hospital-based series of patients with triple-negative breast cancer or serous ovarian cancer compared with healthy controls. The ATAD5 coding and adjacent splice site regions were analyzed by targeted next-generation sequencing of DNA samples from 273 cancer patients, including 114 patients with triple-negative breast cancer and 159 patients with serous epithelial ovarian cancer, and from 276 healthy females. Among 42 different variants identified, twenty-two were rare missense substitutions, of which 14 were classified as pathogenic by at least one in silico prediction tool. Three of four novel missense substitutions (p.S354I, p.H974R and p.K1466N) were predicted to be pathogenic and were all identified in ovarian cancer patients. Overall, rare missense variants with predicted pathogenicity tended to be enriched in ovarian cancer patients (14/159) versus controls (11/276) (p = 0.05, 2df). While truncating germ-line variants in ATAD5 were not detected, it remains possible that several rare missense variants contribute to genetic susceptibility toward epithelial ovarian carcinomas.
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany; Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Macedonia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Maleva Kostovska
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany; Clinics of Radiation Oncology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bogdanova
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schürmann
authors.affiliation: Genome Analytics Group, Helmholtz Center for Infectious Diseases, Inhoffenstraße 7, D-38124 Braunschweig, Germany.
authors.forename: Sabin
authors.initials: S
authors.lastname: Bhuju
authors.affiliation: Genome Analytics Group, Helmholtz Center for Infectious Diseases, Inhoffenstraße 7, D-38124 Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Gynecology, Jena University Hospital - Friedrich Schiller University Jena, Bachstraße 18, D-07743 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.affiliation: Clinics of Obstetrics and Gynecology, Sauerbruchstraße 7, D-38440 Wolfsburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Liebrich
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klapdor
authors.affiliation: Clinics of Radiation Oncology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Tjoung-Won
authors.initials: TW
authors.lastname: Park-Simon
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillemanns
authors.affiliation: Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Macedonia.
authors.forename: Dijana
authors.initials: D
authors.lastname: Plaseska-Karanfilska
authors.affiliation: Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany. Electronic address: doerk.thilo@mh-hannover.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D020125:Mutation, Missense; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D012307:Risk Factors; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D055815:Young Adult
chemical_list: C546328:ATAD5 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: ATAD5; Mutations; Serous ovarian cancer; Triple-negative breast cancer