Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: Potential role in progression

Abstract

Recurrent karyotypic abnormalities are a characteristic feature of cervical cancer (CC) cells, which may result in deregulated expression of important genes that contribute to tumor initiation and progression. To examine the role of gain of the long arm of chromosome 20 (20q), one of the common chromosomal gains in CC, we evaluated CC at various stages of progression using single nucleotide polymorphism (SNP) array, gene expression profiling, and fluorescence in situ hybridization (FISH) analyses. This analysis revealed copy number increase (CNI) of 20q in >50% of invasive CC and identified two focal amplicons at 20q11.2 and 20q13.13 in a subset of tumors. We further demonstrate that the acquisition of 20q gain occurs at an early stage in CC development and the high-grade squamous intraepithelial lesions (HSIL) that exhibit 20q CNI are associated (P = 0.05) with persistence or progression to invasive cancer. We identified a total of 26 overexpressed genes as consequence of 20q gain (N = 14), as targets of amplicon 1 (N = 9; two genes also commonly expressed with 20q gain) and amplicon 2 (N = 6; one gene also commonly expressed with 20q gain). These include a number of functionally important genes in cell cycle regulation (E2F1, TPX2, KIF3B, PIGT, and B4GALT5), nuclear function (CSEL1), viral replication (PSMA7 and LAMA5), methylation and chromatin remodeling (ASXL1, AHCY, and C20orf20), and transcription regulation (TCEA2). Our findings implicate a role for these genes in CC tumorigenesis, represent an important step toward the development of clinically significant biomarkers, and form a framework for testing as molecular therapeutic targets.

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

“…Aurora-A, on the other hand, activates PLK1 controlling mitotic entry and checkpoint recovery (36,37). Aurora-A, TPX2 and PLK1 have been found frequently overexpressing in human cancers, and their deregulations have been implicated in the induction of genomic instability (38)(39)(40). We observed elevated expressions of Tpx2 and Plk1, at varying levels, in the transgenic mouse mammary tumors ( Figure 1D).…”

Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer

“…We therefore compared gene expression profiles in ovarian and cervical cancer samples with their respective normal tissues (Scotto et al 2008;Mok et al 2009). In both cases, we observed that agePCGTs exhibited average expression profiles that were significantly lower in cancer compared with normal tissue (Fig.…”

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

“…In contrast, the genetic changes associated with CIN and CxSCC have been extensively studied, most recently using array-based methods (Hidalgo et al, 2005;Wilting et al, 2006Wilting et al, , 2009Choi et al, 2007;Kloth et al, 2007;Scotto et al, 2008a, b).…”

“…It has been used to investigate the molecular pathogenesis of various human cancers, including cutaneous SCC (Purdie et al, 2007(Purdie et al, , 2009) and cervical cancer (Kloth et al, 2007;Scotto et al, 2008a, b). Here, for the first time, we have applied high-resolution microarray analysis to vulval squamous neoplasia to compare the pattern of genetic changes occurring during the development of hrHPV-associated VSCC with those alterations previously identified during cervical carcinogenesis.…”