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Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
  1. Jan Hauke1,
  2. Eric Hahnen1,
  3. Stephanie Schneider2,
  4. Alexander Reuss3,
  5. Lisa Richters1,
  6. Stefan Kommoss4,
  7. André Heimbach5,
  8. Frederik Marmé6,
  9. Sandra Schmidt1,
  10. Katharina Prieske7,
  11. Heidrun Gevensleben8,
  12. Alexander Burges9,
  13. Julika Borde10,
  14. Nikolaus De Gregorio11,
  15. Peter Nürnberg12,13,
  16. Ahmed El-Balat14,
  17. Holger Thiele12,15,
  18. Felix Hilpert16,17,
  19. Janine Altmüller12,15,
  20. Werner Meier18,
  21. Dimo Dietrich19,
  22. Rainer Kimmig20,
  23. Birgid Schoemig-Markiefka21,
  24. Karin Kast22,23,
  25. Elena Braicu24,
  26. Klaus Baumann25,26,
  27. Christian Jackisch27,
  28. Tjoung-Won Park-Simon28,
  29. Corinna Ernst1,
  30. Lars Hanker29,
  31. Jacobus Pfisterer30,
  32. Andreas Schnelzer31,32,
  33. Andreas du Bois2,
  34. Rita K Schmutzler1,
  35. Philipp Harter2
  1. 1 Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany
  2. 2 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evangelische Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
  3. 3 Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany
  4. 4 Department of Women's Health, University Hospital Tuebingen, Tuebingen, Germany
  5. 5 Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
  6. 6 National Center for Tumor Disease, Department of Gynecology, University of Heidelberg, Heidelberg, Germany
  7. 7 Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  8. 8 Institute of Pathology, University Hospital Bonn, Bonn, Germany
  9. 9 Department of Gynecology, University Hospital Munich-Großhadern, Munich, Germany
  10. 10 Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany
  11. 11 Department of Gynecology and Obstetrics, University Hospital, Universität Ulm, Ulm, Germany
  12. 12 Cologne Center for Genomics (CCG) & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
  13. 13 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  14. 14 Department of Gynecology, University of Frankfurt, Frankfurt, Germany
  15. 15 Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany
  16. 16 Department of Gynecology, University of Kiel, Kiel, Germany
  17. 17 Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany
  18. 18 Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Duesseldorf, Germany
  19. 19 Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
  20. 20 Department of Gynecology, University of Essen, Essen, Germany
  21. 21 Institute of Pathology, University Hospital Cologne, Cologne, Germany
  22. 22 Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  23. 23 German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Heidelberg, Germany
  24. 24 Department of Gynecology and Gynecological Oncology, Charité, Berlin, Germany
  25. 25 Department of Gynecology, Gynecologic Endocrinology and Oncology, University of Gießen and Marburg GmbH, Marburg, Germany
  26. 26 Department of Gynecology and Obstetrics, Klinikum Ludwigshafen, Ludwigshafen, Germany
  27. 27 Department of Gynecology and Obstetrics, Sana Klinikum, Offenbach, Germany
  28. 28 Department of Gynecology, Hannover Medical School, Hannover, Germany
  29. 29 Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
  30. 30 Gynecologic Oncology Center, Kiel, Germany
  31. 31 Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
  32. 32 Department of Obstetrics and Gynecology, RoMed Klinikum Rosenheim, Rosenheim, Germany
  1. Correspondence to Dr Eric Hahnen, Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne 50931, Germany; eric.hahnen{at}uk-koeln.de

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

  • ovarian cancer
  • targeted therapy
  • methylation
  • somatic variant
  • germline variant
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Footnotes

  • Contributors JH and EH contributed equally to this work; study concept and design: JH, EH, ADB, RKS and PH; acquisition, analysis and interpretation of data: JH, EH, StS, AR, LR, SK, AH, FM, SaS, KP, HG, AdB, JB, NDG, PN, AE-B, HT, FH, JA, WM, DD, RK, BS-M, KK, EB, KB, CJ, T-WP-S, CE, LH, JP and AS; drafting the manuscript: JH and EH; critical revision of the manuscript for important intellectual content: StS, AR, LR, SK, AH, FM, SaS, KP, HG, AB, JB, NDG, PN, AE-B, HT, FH, JA, WM, DD, RK, BS-M, KK, EB, KB, CJ, T-WP-S, CE, LH, JP, AS, AdB, RKS and PH; accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors; final approval of the submitted manuscript: all authors; obtained funding: PH; study supervision: EH and PH; administrative, technical or material support: all authors.

  • Funding The study was funded by AstraZeneca, AGO Research GmbH.

  • Competing interests EH: honoraria: AstraZeneca; consulting or advisory role: AstraZeneca; research funding: Astra Zeneca (Inst). SS: honoraria: Roche; consulting or advisory role: Tesaro. KK: honoraria: Roche, Pfizer and AstraZeneca. JP: honoraria: Roche Pharma AG; consulting or advisory role: Amgen, AstraZeneca, Coherus Bioscience, DeciBio, F. Hoffmann-La Roche, Pharmamar, Shield Therapeutics, Simon Kucher & Partner, Taylor Wessing LLP and Tesaro; research funding: Astra Zeneca, Hoffmann-La Roche and Tesaro; travel, accommodations and expenses: Amgen, Astra Zeneca, F. Hoffmann-La Roche and Tesaro. AS: honoraria: TEVA and Gedeon Richter; consulting or advisory role: Astra Zeneca and Roche. SK: honoraria: AstraZeneca and Roche; consulting or advisory role: Roche. KP: travel and research funding: Medac Oncology; honoraria: AstraZeneca and Roche. DD is a consultant for AJ Innuscreen GmbH (Berlin, Germany), a 100% daughter company of Analytik Jena AG (Jena, Germany) and receives royalties from product sales (innuCONVERT kits). AdB: consulting or advisory role: AstraZeneca, Pfizer, Pharmamar, Roche/Genentech, Advaxis, Tesaro, Genmab, Clovis and Biocad. RKS: honoraria: AstraZeneca; consulting or advisory role: AstraZeneca; research funding: AstraZeneca (Inst); patents, royalties, other intellectual property: University of Cologne. CK: consulting and advisory role: AstraZeneca and Roche/Genentech. PH: consulting or advisory role: AstraZeneca, Roche/Genentech, Tesaro, Clovis, Pharmamar Lilly and Sotio; research funding: AstraZeneca (Inst); travel, accommodations and expenses: Medac.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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