Integrated Copy Number and Expression Analysis Identifies Profiles of Whole-Arm Chromosomal Alterations and Subgroups with Favorable Outcome in Ovarian Clear Cell Carcinomas

Abstract

Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis.

Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

“…Ovarian cancer samples and genomic cDNA were obtained, and expression array analysis was performed as previously described [35]. We use probe set 210094_s_at (GeneChip Human Genome U133 Plus 2.0 Array, Affymetrix, CA, USA) to measure patient PARD3 mRNA levels.…”

MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53

“…The high proportion of carcinoma cells (>50%) in each sample was confirmed by a pathologist as described previously [51]. All 91 patients received primary surgery followed by 6-8 cycles of chemotherapy with paclitaxel and carboplatin.…”

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

“…Interestingly, activation of either the PI3K pathway or the RTK pathway was associated with better OS, although this finding needs to be validated independently. Emerging evidence from an evaluation of 25 OCCC samples for gene expression changes and chromosomal instability suggests that OCCCs may cluster into 3 prognostic groups . Compared with HGSOCs, most OCCCs are characterized by considerably fewer CNAs, and mutations in TP53 and BRCA1 / BRCA2 genes are uncommon .…”