Cytogenetic alterations in ovarian clear cell carcinoma detected by comparative genomic hybridisation

Abstract

Ovarian clear cell carcinoma (OCCC) accounts for a small but significant proportion of all ovarian cancers and is a distinct clinical and pathological entity. It tends to be associated with poorer response rates to chemotherapy and with a worse prognosis. Little is known about possible underlying genetic changes. DNA extracted from paraffin-embedded samples of 18 pure OCCC cases was analysed for genetic imbalances using comparative genomic hybridisation (CGH). All of the 18 cases showed genomic alterations. The mean number of alterations detected by CGH was 6 (range 1 -15) indicating a moderate level of genetic instability. Chromosome deletions were more common than amplifications. The most prominent change involved chromosome 9 deletions in 10 cases (55%). This correlates with changes seen in other epithelial ovarian cancers. This deletion was confirmed using microsatellite markers to assess loss of heterozygosity (LOH) at four separate loci on chromosome 9. The most distinct region of loss detected was around the IFNA marker at 9p21 with 41% (11 out of 27cases) LOH. Other frequent deletions involved 1p (five out of 18; 28%); 11q (four out of 18; 22%) and 16 (five out of 18; 28%). Amplification was most common at chromosome 3 (six out of 18; 33%); 13q (four out of 18; 22%) and 15 (three out of 18; 17%). No high-level amplifications were identified. These features may serve as useful prognostic indicators in the management of OCCC.

PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas

“…In particular, we observed gains of 8q, 17q, and 20q and losses on 9p, 11q, 16p/q, and 19p in >30% of the cell lines. Similar gains and losses in these regions with frequencies of >20% have previously been reported in ovarian clear cell carcinomas (9,11,12). Indeed, cell lines and phenotypically matched primary tumors have been shown to have similar molecular features (15), and the selection of optimal in vitro models of specific subtypes of primary cancers can be achieved by matching the aCGH and gene expression profiles of these tumors with those of the well-characterized cell lines (6,14).…”

“…31). 12 The Ingenuity Pathway Analysis software 13 was used to analyze pathways and networks that were significantly enriched for genes whose expression correlated with copy number gains/amplifications and losses in ovarian clear cell carcinoma cell lines. The list of genes overexpressed when gained or amplified and down-regulated when lost were independently mapped to networks and canonical pathways available in the Ingenuity database and ranked by score.…”

“…Nonetheless, frequent gains of 8q (9,10), 17q (9,11), which has been associated with poorer prognosis in ovarian clear cell carcinoma, and 20q (9), and loss of 9p (12) have been reported. Importantly, very few high-resolution CGH studies have been done in ovarian clear cell carcinoma (13) and no candidate therapeutic targets have hitherto been clearly identified and validated in these studies.…”

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma

“…The accumulated evidence from a variety of disciplines indicates that clear cell carcinoma also has several distinct cytogenetic, molecular genetic, and gene expression alterations when compared to other more common surface epithelial neoplasms. 8,[25][26][27][28] Not surprisingly, some of the differentially expressed genes found on mRNA expression studies of ovarian carcinoma fall into a proliferation cluster or cluster with genes encoding proteins involved in cell cycle progression. 26 Misregulation of the G1/S transition in the cell cycle is a fundamental component of the cellular transformation process and G1/S regulatory defects have been reported in a variety of human malignancies.…”

Molecular characterization of a t(9;12)(p21;q13) balanced chromosome translocation in combination with integrative genomics analysis identifies C9orf14 as a candidate tumor‐suppressor

“…Analysis of a publicly available ovarian expression data set (Lu et al, 2004) revealed downregulation of C9orf14 in serous carcinomas relative to normal ovarian surface epithelium (P < 0.05). This observation, together with data describing the genetic loss of 9p21 in ovarian clear cell carcinomas (Dent et al, 2003), might also suggest that C9orf14 is involved in ovarian tumorigenesis.…”