Ovarian Cancer-Specific -like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial.

Alexander Burges, Rita K Schmutzler, Sabine C Linn, Philipp Harter, Eric Hahnen, Lodewyk F Wessels, Petra M Nederlof, Andreas du Bois, Jan Hauke, Nikolaus de Gregorio, Agnes Jager, Dimo Dietrich, Patricia C Ewing-Graham, Philip C Schouten, Carolien H M van Deurzen, Katharina Prieske, Esther Scheerman, Sandra Schmidt, Esther H Lips, Frederik Marmé, Roelof J C Kluin, Corinna Ernst, Ewald van Dijk, Stefan Kommoss, Daniel J Vis, Lisa Richters

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2022;27(23):6559-6569

PMID: 34593530

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Abstract

PURPOSE

Previously, we developed breast cancer like and -like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated and like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. We analyzed DNA copy-number profiles of germline - and -mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed -like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883).

RESULTS

The detection rate of the -like classifier for mutations and promoter hypermethylation was 95.6%. The -like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the -like tumors could be explained by (epi)genetic alterations in , germline mutations and alterations in other genes involved in HR. Around half of the non--mutated ovarian cancer cases displayed a -like phenotype.

CONCLUSIONS

The newly trained classifiers detected most -mutated and methylated cancers and all tumors harboring a germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be -like.

Address: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [email protected].; Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.; Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.; Genomics Core Facility, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.; Department of Gynecologic Oncology, Medical Faculty Mannheim, University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.; Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.; Department of Gynecology and Obstetrics, University Hospital Munich-Großhadern, Munich, Germany.; Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.; Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands.; Department of Gynecology and Obstetrics, University Hospital, University of Ulm, Ulm, Germany.; Department of Gynecology and Gynecologic Oncology, Ev. Kliniken Essen-Mitte, Essen, Germany.; Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, the Netherlands.; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.

DOI: 10.1158/1078-0432.CCR-21-1673

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MeSH Terms: BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Genes, BRCA2, Germ-Line Mutation, Homologous Recombination, Humans, Mutation, Ovarian Neoplasms