Universität zu Köln

Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, van Dijk, Ewald, Ernst, Corinna ORCID: 0000-0001-7756-8815, Kluin, Roelof J. C., Marme, Frederik ORCID: 0000-0002-6591-3367, Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, van Deurzen, Carolien H. M., Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, de Gregorio, Nikolaus, Hauke, Jan ORCID: 0000-0001-8236-4075, du Bois, Andreas, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C. and Schmutzler, Rita K. (2021). Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial. Clin. Cancer Res., 27 (23). S. 6559 - 6570. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

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 Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schouten, Philip C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richters, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Vis, Daniel J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kommoss, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED van Dijk, Ewald UNSPECIFIED UNSPECIFIED UNSPECIFIED Ernst, Corinna UNSPECIFIED orcid.org/0000-0001-7756-8815 UNSPECIFIED Kluin, Roelof J. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marme, Frederik UNSPECIFIED orcid.org/0000-0002-6591-3367 UNSPECIFIED Lips, Esther H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheerman, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Prieske, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED van Deurzen, Carolien H. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Burges, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Ewing-Graham, Patricia C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietrich, Dimo UNSPECIFIED UNSPECIFIED UNSPECIFIED Jager, Agnes UNSPECIFIED UNSPECIFIED UNSPECIFIED de Gregorio, Nikolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Hauke, Jan UNSPECIFIED orcid.org/0000-0001-8236-4075 UNSPECIFIED du Bois, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Nederlof, Petra M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wessels, Lodewyk F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Harter, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Linn, Sabine C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-602711
DOI:	10.1158/1078-0432.CCR-21-1673
Journal or Publication Title:	Clin. Cancer Res.
Volume:	27
Number:	23
Page Range:	S. 6559 - 6570
Date:	2021
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BREAST-CANCER; MAINTENANCE THERAPY; GENOMIC LOSS; OLAPARIB; PROFILE; REPAIR; CHEMOTHERAPY; MULTICENTER; CARCINOMA; RUCAPARIB Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60271