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≥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.

Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

“…47 A critical region including REXO1L1 and a number of candidate genes is amplified in a variety of cancers 48 but overexpression of REXO1L1 in cancer has apparently been recorded only once. 49 In conclusion, we have confirmed the existence of the 8q21.2 EV and mapped the variation to a region containing the 8q21.2 VNTR arrays with multiple copies of a 12-kb repeat and the REXO1L1 gene cluster. We propose that expansion of this VNTR explains the microscopic visibility of the 8q21.2 EVs, which need to be distinguished from pathogenic imbalances especially at prenatal diagnosis.…”

Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

“…Further work should focus on the transformative effects of other genetic alterations strongly associated with HGSOC, such as BRCA1/2 mutations and genes that recurrently undergo DNA copy-number changes such as CCNE, EVI1, PTK2, ERBB2, PRKCI, NF1, and PTEN (23,29,30). Our model also serves as a platform for investigating the many candidate oncogenes and tumor suppressors now being identified by The Cancer Genome Atlas and other large-scale genomic analyses of HGSOC (29,36,37).…”

Targeting Protein for Xenopus Kinesin-like Protein 2 (TPX2) Regulates γ-Histone 2AX (γ-H2AX) Levels upon Ionizing Radiation

“…Moreover, TPX2 levels are altered in cancers associated with aberrant cellular responses to DNA damage and genomic instability (12)(13)(14)(15)(16)(17)(18)(19). These observations raise the question as to whether TPX2 is involved in the DNA damage response.…”

“…), and amplification of the TPX2 gene has been suggested to promote the progression of colorectal malignancies (12)(13)(14)(15)(16)(17)(18)(19). Conversely, TPX2 haploinsufficiency, leading to decreased levels of TPX2, significantly increases the propensity for the development of tumors in mice (20).…”