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Ovarian cancer-specific BRCA-like copy-number aberration classifiers detect mutations associated with homologous recombination deficiency in the AGO-TR1 trial

Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in...

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Main Authors: Schouten, Philip (Author) , Richters, Lisa (Author) , Vis, Daniel J. (Author) , Kommoss, Stefan (Author) , Dijk, Ewald van (Author) , Ernst, Corinna (Author) , Kluin, Roelof J. C. (Author) , Marmé, Frederik (Author) , Lips, Esther H. (Author) , Schmidt, Sandra (Author) , Scheerman, Esther (Author) , Prieske, Katharina (Author) , Deurzen, Carolien H. M. van (Author) , Burges, Alexander (Author) , Ewing-Graham, Patricia C. (Author) , Dietrich, Dimo (Author) , Jager, Agnes (Author) , Gregorio, Nikolaus de (Author) , Hauke, Jan (Author) , Bois, Andreas du (Author) , Nederlof, Petra M. (Author) , Wessels, Lodewyk F. (Author) , Hahnen, Eric (Author) , Harter, Philipp (Author) , Linn, Sabine C. (Author) , Schmutzler, Rita K. (Author)
Format: Article (Journal)
Language:English
Published: September 30, 2021
In: Clinical cancer research
Year: 2021, Volume: 27, Issue: 23, Pages: 6559-6569
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-21-1673
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-21-1673
Verlag, lizenzpflichtig, Volltext: https://clincancerres.aacrjournals.org/content/27/23/6559
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Author Notes:Philip C. Schouten, Lisa Richters, Daniel J. Vis, Stefan Kommoss, Ewald van Dijk, Corinna Ernst, Roelof J.C. Kluin, Frederik Marmé, Esther H. Lips, Sandra Schmidt, Esther Scheerman, Katharina Prieske, Carolien H.M. van Deurzen, Alexander Burges, Patricia C. Ewing-Graham, Dimo Dietrich, Agnes Jager, Nikolaus de Gregorio, Jan Hauke, Andreas du Bois, Petra M. Nederlof, Lodewyk F. Wessels, Eric Hahnen, Philipp Harter, Sabine C. Linn, and Rita K. Schmutzler
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Summary:Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. - Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-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 BRCA1/2-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 BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. - Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
Item Description:Gesehen am 21.01.2022
Physical Description:Online Resource
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-21-1673

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