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Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).
Hauke, Jan; Hahnen, Eric; Schneider, Stephanie; Reuss, Alexander; Richters, Lisa; Kommoss, Stefan; Heimbach, André; Marmé, Frederik; Schmidt, Sandra; Prieske, Katharina; Gevensleben, Heidrun; Burges, Alexander; Borde, Julika; De Gregorio, Nikolaus; Nürnberg, Peter; El-Balat, Ahmed; Thiele, Holger; Hilpert, Felix; Altmüller, 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; Harter, Philipp.
Affiliation
  • Hauke J; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
  • Hahnen E; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany eric.hahnen@uk-koeln.de.
  • Schneider S; Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evangelische Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
  • Reuss A; Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.
  • Richters L; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
  • Kommoss S; Department of Women's Health, University Hospital Tuebingen, Tuebingen, Germany.
  • Heimbach A; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • Marmé F; National Center for Tumor Disease, Department of Gynecology, University of Heidelberg, Heidelberg, Germany.
  • Schmidt S; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
  • Prieske K; Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Gevensleben H; Institute of Pathology, University Hospital Bonn, Bonn, Germany.
  • Burges A; Department of Gynecology, University Hospital Munich-Großhadern, Munich, Germany.
  • Borde J; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
  • De Gregorio N; Department of Gynecology and Obstetrics, University Hospital, Universität Ulm, Ulm, Germany.
  • Nürnberg P; Cologne Center for Genomics (CCG) & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • El-Balat A; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • Thiele H; Department of Gynecology, University of Frankfurt, Frankfurt, Germany.
  • Hilpert F; Cologne Center for Genomics (CCG) & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Altmüller J; Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
  • Meier W; Department of Gynecology, University of Kiel, Kiel, Germany.
  • Dietrich D; Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany.
  • Kimmig R; Cologne Center for Genomics (CCG) & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Schoemig-Markiefka B; Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
  • Kast K; Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Duesseldorf, Germany.
  • Braicu E; Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
  • Baumann K; Department of Gynecology, University of Essen, Essen, Germany.
  • Jackisch C; Institute of Pathology, University Hospital Cologne, Cologne, Germany.
  • Park-Simon TW; Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Ernst C; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Heidelberg, Germany.
  • Hanker L; Department of Gynecology and Gynecological Oncology, Charité, Berlin, Germany.
  • Pfisterer J; Department of Gynecology, Gynecologic Endocrinology and Oncology, University of Gießen and Marburg GmbH, Marburg, Germany.
  • Schnelzer A; Department of Gynecology and Obstetrics, Klinikum Ludwigshafen, Ludwigshafen, Germany.
  • du Bois A; Department of Gynecology and Obstetrics, Sana Klinikum, Offenbach, Germany.
  • Schmutzler RK; Department of Gynecology, Hannover Medical School, Hannover, Germany.
  • Harter P; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
J Med Genet ; 56(9): 574-580, 2019 09.
Article in En | MEDLINE | ID: mdl-30979843
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 (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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Full text: 1 Database: MEDLINE Main subject: Ovarian Neoplasms / Sequence Deletion / Genetic Predisposition to Disease / Genetic Association Studies Type of study: Diagnostic_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Year: 2019 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Ovarian Neoplasms / Sequence Deletion / Genetic Predisposition to Disease / Genetic Association Studies Type of study: Diagnostic_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Year: 2019 Type: Article