Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha.
BACKGROUND
Copy number gains and amplifications are characteristic feature of cervical cancer (CC) genomes for which the underlying mechanisms are unclear. These changes may possess oncogenic properties by deregulating tumor-related genes. Gain of short arm of chromosome 5 (5p) is the most frequent karyotypic change in CC.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pathology, Columbia University Medical Center, New York, New York, USA. ls339@columbia.edu
Luigi
L
Scotto
Gopeshwar
G
Narayan
Subhadra V
SV
Nandula
Shivakumar
S
Subramaniyam
Andreas M
AM
Kaufmann
Jason D
JD
Wright
Bhavana
B
Pothuri
Mahesh
M
Mansukhani
Achim
A
Schneider
Hugo
H
Arias-Pulido
Vundavalli V
VV
Murty
D045744:Cell Line, Tumor; D002895:Chromosomes, Human, Pair 5; D003105:Colombia; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D005858:Germany; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009361:Neoplasm Invasiveness; D009518:New York; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D015203:Reproducibility of Results; D043244:Ribonuclease III / Q000235:genetics*; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology
C517918:DROSHA protein, human; D043244:Ribonuclease III