Hauke, Jan, Hahnen, Eric, Schneider, Stephanie, Reuss, Alexander, Richters, Lisa, Kommoss, Stefan, Heimbach, Andre, Marme, Frederik, Schmidt, Sandra, Prieske, Katharina, Gevensleben, Heidrun, Burges, Alexander, Borde, Julika, De Gregorio, Nikolaus, Nuernberg, Peter, El-Balat, Ahmed, Thiele, Holger, Hilpert, Felix, Altmueller, Janine, Meier, Werner, Dietrich, Dimo, Kimmig, Rainer, Schoemig-Markiefka, Birgid, Kast, Karin, Braicu, Elena, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Ernst, Corinna, Hanker, Lars, Pfisterer, Jacobus, Schnelzer, Andreas, du Bois, Andreas, Schmutzler, Rita K. and Harter, Philipp (2019). Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883). J. Med. Genet., 56 (9). S. 574 - 581. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

Background For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? Methods Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AG O-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. Results The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. Conclusion Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reuss, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kommoss, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimbach, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marme, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prieske, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gevensleben, HeidrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burges, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borde, JulikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Gregorio, NikolausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El-Balat, AhmedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilpert, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, WernerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietrich, DimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kimmig, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoemig-Markiefka, BirgidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braicu, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park-Simon, Tjoung-WonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ernst, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanker, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfisterer, JacobusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnelzer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
du Bois, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harter, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-141873
DOI: 10.1136/jmedgenet-2018-105930
Journal or Publication Title: J. Med. Genet.
Volume: 56
Number: 9
Page Range: S. 574 - 581
Date: 2019
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOLOGOUS RECOMBINATION GENES; PROMOTER METHYLATION; SPORADIC BREAST; BRCA1; MUTATIONS; HYPERMETHYLATION; SENSITIVITY; FREQUENCY; SURVIVAL; POLYMERASEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14187

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