Identification of candidate growth promoting genes in ovarian cancer through integrated copy number and expression analysis

Abstract

Ovarian cancer is a disease characterised by complex genomic rearrangements but the majority of the genes that are the target of these alterations remain unidentified. Cataloguing these target genes will provide useful insights into the disease etiology and may provide an opportunity to develop novel diagnostic and therapeutic interventions. High resolution genome wide copy number and matching expression data from 68 primary epithelial ovarian carcinomas of various histotypes was integrated to identify genes in regions of most frequent amplification with the strongest correlation with expression and copy number. Regions on chromosomes 3, 7, 8, and 20 were most frequently increased in copy number (> 40% of samples). Within these regions, 703/1370 (51%) unique gene expression probesets were differentially expressed when samples with gain were compared to samples without gain. 30% of these differentially expressed probesets also showed a strong positive correlation (r > or =0.6) between expression and copy number. We also identified 21 regions of high amplitude copy number gain, in which 32 known protein coding genes showed a strong positive correlation between expression and copy number. Overall, our data validates previously known ovarian cancer genes, such as ERBB2, and also identified novel potential drivers such as MYNN, PUF60 and TPX2.

Figure 1. Overview of genomic aberrations in the ovarian cancer dataset (N = 72).

Frequency of occurrence of genomic gains (yellow) and losses (blue) across the genome, depicted in chromosome order from 1p to Xq.

Figure 2. Detailed view of chromosomes showing frequent gains.

Frequent gains occur on chromosomes 3, 7, 8 and 20, with each point indicating the frequency of gain of a CN segment. The red line in all panels indicates the 40% frequency threshold.

Figure 3. Correlation between copy number and expression for a frequently gained region on cytoband 3q26.2.

A. Frequency of copy number gain on chromosome 3 from p-ter at left to q-ter at right as indicated by the ideogram. B. Genes on Chr3: 169.209–172.478 Mbp, a region gained in 60% (41/68) of all samples, including genes previously associated with ovarian cancer (PRKCI, MECOM or MDS1/EVI1) and potentially novel oncogenes (MYNN). C. A volcano plot presenting the results of expression analyses between amplified and unamplified samples in this region. The genes in the top right corner are significantly overexpressed in samples with copy number gain (p<0.05; above the red line at –logP 4.32) compared to samples without copy number change (selected genes are labelled). For full list of differentially expressed genes see Table S5. D. Plot comparing copy number and expression in all samples for the gene MYNN that showed the highest correlation (r = 0.74, Pearson's test) between copy number and expression for this region on 3q26.2.