TY  - JOUR
A1  - Harter, Philipp
A1  - Hauke, Jan
A1  - Heitz, Florian
A1  - Reuss, Alexander
A1  - Kommoss, Stefan
A1  - Marmé, Frederik
A1  - Heimbach, André
A1  - Prieske, Katharina
A1  - Richters, Lisa
A1  - Burges, Alexander
A1  - Neidhardt, Guido
A1  - Gregorio, Nikolaus de
A1  - Balat, Ahmed el-
A1  - Hilpert, Felix
A1  - Meier, Werner
A1  - Kimmig, Rainer
A1  - Kast, Karin
A1  - Sehouli, Jalid
A1  - Baumann, Klaus
A1  - Jackisch, Christian
A1  - Park-Simon, Tjoung-Won
A1  - Hanker, Lars
A1  - Kröber, Sandra
A1  - Pfisterer, Jacobus
A1  - Gevensleben, Heidrun
A1  - Schnelzer, Andreas
A1  - Dietrich, Dimo
A1  - Neunhöffer, Tanja
A1  - Krockenberger, Mathias Heinric
A1  - Brucker, Sara
A1  - Nürnberg, Peter
A1  - Thiele, Holger
A1  - Altmüller, Janine
A1  - Lamla, Josefin
A1  - Elser, Gabriele
A1  - Du Bois, Andreas
A1  - Hahnen, Eric Thomas
A1  - Schmutzler, Rita Katharina
T1  - Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)
T2  - PLoS one
N2  - 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.
KW  - Genetic causes of cancer
KW  - Ovarian cancer
KW  - Histology
KW  - Cancer detection and diagnosis
KW  - Genetic testing
KW  - Human genetics
KW  - Breast cancer
KW  - Oncology
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45125
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-451256
SN  - 1932-6203
N1  - Copyright: © 2017 Harter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 12
IS  - (10): e0186043
SP  - 1
EP  - 12
PB  - PLoS
CY  - Lawrence, Kan.
ER  -