Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer.

Abstract

OBJECTIVE:

Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response.

METHODS:

SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227).

RESULTS:

We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26).

CONCLUSIONS:

We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.

• Authors: Evelyn Despierre, Matthieu Moisse, Betül Yesilyurt, Jalid Sehouli, Ioana Braicu, Sven Mahner, Dan Cacsire Castillo-Tong, Robert Zeillinger, Sandrina Lambrechts, Karin Leunen, Frédéric Amant, Philippe Moerman, Diether Lambrechts, Ignace Vergote
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 135 Issue 3 Pg. 415-22 (Dec 2014) ISSN: 1095-6859 [Electronic] United States
• PMID: 25281495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Organoplatinum Compounds

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics)
• Carcinoma, Ovarian Epithelial
• Cohort Studies
• Female
• Gene Dosage
• Humans
• Middle Aged
• Neoplasms, Glandular and Epithelial (drug therapy, genetics)
• Organoplatinum Compounds (therapeutic use)
• Ovarian Neoplasms (drug therapy, genetics)
• Polymorphism, Single Nucleotide
• Prognosis