Harter, Philipp, Hauke, Jan, Heitz, Florian ORCID: 0000-0002-2412-0352, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhoeffer, Tanja, Krockenberger, Mathias, Brucker, Sara Y., Nuernberg, Peter, Thiele, Holger, Altmueller, Janine, Lamla, Josefin, Elser, Gabriele, du Bois, Andreas, Hahnen, Eric and Schmutzler, Rita (2017). Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One, 12 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients >= 60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. Conclusions 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Harter, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heitz, FlorianUNSPECIFIEDorcid.org/0000-0002-2412-0352UNSPECIFIED
Reuss, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kommoss, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marme, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimbach, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prieske, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burges, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neidhardt, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Gregorio, NikolausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El-Balat, AhmedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilpert, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, WernerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kimmig, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sehouli, JalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park-Simon, Tjoung-WonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanker, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroeber, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfisterer, JacobusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gevensleben, HeidrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnelzer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietrich, DimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neunhoeffer, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krockenberger, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brucker, Sara Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamla, JosefinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elser, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
du Bois, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-214095
DOI: 10.1371/journal.pone.0186043
Journal or Publication Title: PLoS One
Volume: 12
Number: 10
Date: 2017
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INHERITED MUTATIONS; FALLOPIAN-TUBE; BREAST; SUSCEPTIBILITY; SERIES; WOMEN; SURVIVAL; IMPACT; MODELMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21409

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