Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha

To examine the role of 5p gain, we performed a combination of single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression analyses on invasive cancer and in various stages of CC progression.The SNP and FISH analyses revealed copy number increase (CNI) of 5p in 63% of invasive CC, which arises at later stages of precancerous lesions in CC development. We integrated chromosome 5 genomic copy number and gene expression data to identify key target over expressed genes as a consequence of 5p gain. One of the candidates identified was Drosha (RNASEN), a gene that is required in the first step of microRNA (miRNA) processing in the nucleus. Other 5p genes identified as targets of CNI play a role in DNA repair and cell cycle regulation (BASP1, TARS, PAIP1, BRD9, RAD1, SKP2, and POLS), signal transduction (OSMR), and mitochondrial oxidative phosphorylation (NNT, SDHA, and NDUFS6), suggesting that disruption of pathways involving these genes may contribute to CC progression.Taken together, we demonstrate the power of integrating genomics data with expression data in deciphering tumor-related targets of CNI. Identification of 5p gene targets in CC denotes an important step towards biomarker development and forms a framework for testing as molecular therapeutic targets.The short arm of chromosome 5 (5p) frequently undergoes nonrandom changes in cervical cancer (CC) by exhibiting both copy number increase and deletions. Gain of 5p due to frequent appearance of isochromosome 5p in squamous cell carcinoma has been documented by karyotypic and chromosomal comparative genomic hybridization analyses [1-4]. Paradoxically, 5p also exhibits frequent loss of heterozygosity, which occurs early in the development of CC [5,6]. These findings suggest the presence of important proliferation-regulating genes on chromosome 5p involved in malignant progression of cervical epithelium.Despite the successful use of pap-smear screening programs in early