Identification of Candidate Growth Promoting Genes in Ovarian Cancer through Integrated Copy Number and Expression Analysis

VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e9983. DOI: 10.1371/journal.pone.0009983
Source: PubMed


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.

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Available from: Kylie Gorringe, Aug 21, 2014
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    Oncotarget 11/2013; 4(12). DOI:10.18632/oncotarget.1581 · 6.36 Impact Factor
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    • "Just recently, we generated Zfatf/f-Cd4Cre mice [6], and showed that Zfat-deficient mice exhibited a reduction in the number of peripheral T cells with decreased surface expression of IL-7Rα and T cell antigen receptor (TCR)-stimulation-induced expression of CD25 and IL-2, indicating that Zfat is required for peripheral T cell homeostasis [6]. On the other hand, genetic variants of ZFAT have also been reported to be associated with adult height in Japanese and Korean population [7], [8] and several common diseases including hypertension and cancer [9], [10]. Of great interest is that a genetic variant of ZFAT is reported to be strongly associated with interferon-β responsiveness in multiple sclerosis [11] and the severity of Hashimoto’s disease [12]. "
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    PLoS ONE 10/2013; 8(10):e76254. DOI:10.1371/journal.pone.0076254 · 3.23 Impact Factor
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    • "GSE19539 consisting of 8 clear cell, 14 endometrioid, 6 mucinous, and 39 serous [15]. Blood normal available in the dataset was used for normalization in concordance with the paper. "
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    ABSTRACT: Background Epithelial ovarian cancer is characterized by multiple genomic alterations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and can be broadly categorized into 4 main histotypes of clear cell, endometrioid, mucinous, and serous. To date, histotype-specific copy number alterations have been difficult to elucidate. The difficulty lies in having sufficient sample size in each histotype for statistical analyses. Methods To dissect the heterogeneity of ovarian cancer and identify histotype-specific alterations, we used an in silico hypothesis-driven approach on multiple datasets of epithelial ovarian cancer. Results In concordance with previous studies on global copy number alterations landscape, the study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here significant histotype-specific copy number alterations in ovarian cancer and showed that there is genomic diversity amongst the histotypes. 76 cancer genes were found to be significantly altered with several as potential copy number drivers, including ERBB2 in mucinous, and TPM3 in endometrioid histotypes. ERBB2 was found to have preferential alterations, where it was amplified in mucinous (28.6%) but deleted in serous tumors (15.1%). Validation of ERBB2 expression showed significant correlation with microarray data (p=0.007). There also appeared to be reciprocal relationship between KRAS mutation and copy number alterations. In mucinous tumors where KRAS mutation is common, the gene was not significantly altered. However, KRAS was significantly amplified in serous tumors where mutations are rare in high grade tumors. Conclusions The study demonstrates that the copy number landscape is specific to the histotypes and identification of these alterations can pave the way for targeted drug therapy specific to the histotypes.
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