title: Integrative genomic and network analysis identified novel genes associated with the development of advanced cervical squamous cell carcinoma.
abstract: CSCC is one of the most common cancer affecting women globally. Though it is caused by the infection of hrHPV but long latency period for malignant outcome in only a subset of hrHPV infected women indicates involvement of additional alterations, primarily CNVs. Here, we showed how CNVs played a crucial role in development of advanced tumors (stage III/IV) in Indian patients.
  
  
  
  Initially, high-resolution CGH-SNP microarray analysis pointed out frequent CNVs followed by significantly altered genes. After comparison with TCGA dataset, expressions of the genes were checked in three CSCC datasets to identify key genes followed by Ingenuity® Pathway analysis. Then node effect property analysis was applied on the constructed PPI network to rank the key proteins. Finally, validations in independent samples were performed.
  
  
  
  For the first time, frequent chromosomal amplifications at 3q13.13-3q29, 1p36.11-1p31.1, 1q21.1-1q44 and 5p15.33-5p12 followed by common deletions at 11q14.1-11q25, 2q34-2q37.3, 4p16.3-4p12 and 13q13.3-13q14.3 were identified in Indian CSCC patients. Integrative analysis found 78 key genes including several novel ones, which were mostly associated with 'Cancer' and may regulate DNA repair and metabolic pathways. Analysis showed PARP1 and ATR were among the top ranking protein interactors.
  
  
  
  Frequent amplification and over-expression of ATR and PARP1 were further confirmed in cervical lesions, indicating their association with poor prognosis of advanced CSCC patients.
  
  
  
  Our novel approach identified precise CNVs along with several novel genes within these loci and showed that PARP1 and ATR, having biologically significant interactions, may be involved in development of advanced CSCC.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Roychowdhury
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Sudip
authors.initials: S
authors.lastname: Samadder
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Pijush
authors.initials: P
authors.lastname: Das
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Sapan
authors.initials: S
authors.lastname: Mandloi
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Chandraditya
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: India Screening Group (SCR), Early Detection and Prevention Section (EDP), International Agency for Research on Cancer (IARC), World Health Organization (WHO), Lyon, France.
authors.forename: Partha Sarathi
authors.initials: PS
authors.lastname: Basu
authors.affiliation: Department of Gynaecology Oncology, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Ranajit
authors.initials: R
authors.lastname: Mondal
authors.affiliation: North Bengal Medical College and Hospital, West Bengal, India.
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.affiliation: Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Saroj Gupta Cancer Centre & Research Institute, Kolkata, India. Electronic address: susanta@iicb.res.in.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India. Electronic address: ckpanda.cnci@gmail.com.
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D023281:Genomics; D006801:Humans; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics; D015203:Reproducibility of Results; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology*
keywords: ATR; Cervical cancer; Copy-number variations; PARP1; Protein-protein interaction network