Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)

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

doi:10.1136/jmedgenet-2018-105930

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)

J Med Genet. 2019 Sep;56(9):574-580. doi: 10.1136/jmedgenet-2018-105930. Epub 2019 Apr 12.

Authors

Jan Hauke¹, Eric Hahnen², Stephanie Schneider³, Alexander Reuss⁴, Lisa Richters¹, Stefan Kommoss⁵, André Heimbach⁶, Frederik Marmé⁷, Sandra Schmidt¹, Katharina Prieske⁸, Heidrun Gevensleben⁹, Alexander Burges¹⁰, Julika Borde¹, Nikolaus De Gregorio¹¹, Peter Nürnberg^{12

13}, Ahmed El-Balat¹⁴, Holger Thiele^{12

15}, Felix Hilpert^{16

17}, Janine Altmüller^{12

15}, Werner Meier¹⁸, Dimo Dietrich¹⁹, Rainer Kimmig²⁰, Birgid Schoemig-Markiefka²¹, Karin Kast^{22

23}, Elena Braicu²⁴, Klaus Baumann^{25

26}, Christian Jackisch²⁷, Tjoung-Won Park-Simon²⁸, Corinna Ernst¹, Lars Hanker²⁹, Jacobus Pfisterer³⁰, Andreas Schnelzer^{31

32}, Andreas du Bois³, Rita K Schmutzler¹, Philipp Harter³

Affiliations

¹ Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
² Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany eric.hahnen@uk-koeln.de.
³ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evangelische Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
⁴ Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.
⁵ Department of Women's Health, University Hospital Tuebingen, Tuebingen, Germany.
⁶ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁷ National Center for Tumor Disease, Department of Gynecology, University of Heidelberg, Heidelberg, Germany.
⁸ Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Institute of Pathology, University Hospital Bonn, Bonn, Germany.
¹⁰ Department of Gynecology, University Hospital Munich-Großhadern, Munich, Germany.
¹¹ Department of Gynecology and Obstetrics, University Hospital, Universität Ulm, Ulm, Germany.
¹² Cologne Center for Genomics (CCG) & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹³ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
¹⁴ Department of Gynecology, University of Frankfurt, Frankfurt, Germany.
¹⁵ Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
¹⁶ Department of Gynecology, University of Kiel, Kiel, Germany.
¹⁷ Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany.
¹⁸ Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Duesseldorf, Germany.
¹⁹ Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
²⁰ Department of Gynecology, University of Essen, Essen, Germany.
²¹ Institute of Pathology, University Hospital Cologne, Cologne, Germany.
²² Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²³ German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Heidelberg, Germany.
²⁴ Department of Gynecology and Gynecological Oncology, Charité, Berlin, Germany.
²⁵ Department of Gynecology, Gynecologic Endocrinology and Oncology, University of Gießen and Marburg GmbH, Marburg, Germany.
²⁶ Department of Gynecology and Obstetrics, Klinikum Ludwigshafen, Ludwigshafen, Germany.
²⁷ Department of Gynecology and Obstetrics, Sana Klinikum, Offenbach, Germany.
²⁸ Department of Gynecology, Hannover Medical School, Hannover, Germany.
²⁹ Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
³⁰ Gynecologic Oncology Center, Kiel, Germany.
³¹ Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
³² Department of Obstetrics and Gynecology, RoMed Klinikum Rosenheim, Rosenheim, Germany.

PMID: 30979843
DOI: 10.1136/jmedgenet-2018-105930

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.

Keywords: germline variant; methylation; ovarian cancer; somatic variant; targeted therapy.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein
BRCA2 Protein
Biomarkers, Tumor
Computational Biology / methods
DNA Copy Number Variations
DNA Methylation
Female
Genetic Association Studies* / methods
Genetic Predisposition to Disease*
Genetic Testing
Germ-Line Mutation
High-Throughput Nucleotide Sequencing
Humans
Ovarian Neoplasms / diagnosis
Ovarian Neoplasms / epidemiology
Ovarian Neoplasms / genetics*
Prevalence
Promoter Regions, Genetic
Sequence Deletion*

Substances

BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Biomarkers, Tumor

Associated data

ClinicalTrials.gov/NCT02222883