Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
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...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
12 April 2019
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| In: |
Journal of medical genetics
Year: 2019, Jahrgang: 56, Heft: 9, Pages: 574-580 |
| ISSN: | 1468-6244 |
| DOI: | 10.1136/jmedgenet-2018-105930 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/jmedgenet-2018-105930 Verlag, lizenzpflichtig, Volltext: https://jmg.bmj.com/content/56/9/574 
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| Verfasserangaben: | Jan Hauke, Eric Hahnen, Stephanie Schneider, Alexander Reuss, Lisa Richters, Stefan Kommoss, André Heimbach, Frederik Marmé, Sandra Schmidt, Katharina Prieske, Heidrun Gevensleben, Alexander Burges, Julika Borde, Nikolaus De Gregorio, Peter Nürnberg, Ahmed El-Balat, Holger Thiele, Felix Hilpert, Janine Altmüller, Werner Meier, Dimo Dietrich, Rainer Kimmig, Birgid Schoemig-Markiefka, Karin Kast, Elena Braicu, Klaus Baumann, Christian Jackisch, Tjoung-Won Park-Simon, Corinna Ernst, Lars Hanker, Jacobus Pfisterer, Andreas Schnelzer, Andreas du Bois, Rita K. Schmutzler, Philipp Harter |
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| 245 | 1 | 0 | |a Deleterious somatic variants in 473 consecutive individuals with ovarian cancer |b results of the observational AGO-TR1 study (NCT02222883) |c Jan Hauke, Eric Hahnen, Stephanie Schneider, Alexander Reuss, Lisa Richters, Stefan Kommoss, André Heimbach, Frederik Marmé, Sandra Schmidt, Katharina Prieske, Heidrun Gevensleben, Alexander Burges, Julika Borde, Nikolaus De Gregorio, Peter Nürnberg, Ahmed El-Balat, Holger Thiele, Felix Hilpert, Janine Altmüller, Werner Meier, Dimo Dietrich, Rainer Kimmig, Birgid Schoemig-Markiefka, Karin Kast, Elena Braicu, Klaus Baumann, Christian Jackisch, Tjoung-Won Park-Simon, Corinna Ernst, Lars Hanker, Jacobus Pfisterer, Andreas Schnelzer, Andreas du Bois, Rita K. Schmutzler, Philipp Harter |
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| 520 | |a 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 (AGO-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. - Trial registration number NCT02222883 | ||
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