title: Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia.
abstract: BACKGROUND
  The incidence of and mortality from colorectal cancers (CRC) can be reduced by early detection. Currently there is a lack of established markers to detect early neoplastic changes. We aimed to identify the copy number variations (CNVs) and the associated genes which could be potential markers for the detection of neoplasia in both ulcerative colitis-associated neoplasia (UC-CRN) and sporadic colorectal neoplasia (S-CRN).
  
  
  METHODS
  We employed array comparative genome hybridization (aCGH) to identify CNVs in tissue samples of UC nonprogressor, progressor and sporadic CRC. Select genes within these CNV regions as a panel of markers were validated using quantitative real time PCR (qRT-PCR) method along with the microsatellite instability (MSI) in an independent cohort of samples. Immunohistochemistry (IHC) analysis was also performed.
  
  
  RESULTS
  Integrated analysis showed 10 overlapping CNV regions between UC-Progressor and S-CRN, with the 8q and 12p regions showing greater overlap. The qRT-PCR based panel of MYC, MYCN, CCND1, CCND2, EGFR and FNDC3A was successful in detecting neoplasia with an overall accuracy of 54% in S-CRN compared to that of 29% in UC neoplastic samples. IHC study showed that p53 and CCND1 were significantly overexpressed with an increasing frequency from pre-neoplastic to neoplastic stages. EGFR and AMACR were expressed only in the neoplastic conditions.
  
  
  CONCLUSIONS
  CNVs that are common and unique to both UC-associated and sporadic colorectal neoplasm could be the key players driving carcinogenesis. Comparative analysis of CNVs provides testable driver aberrations but needs further evaluation in larger cohorts of samples. These markers may help in developing more effective neoplasia-detection strategies during screening and surveillance programs.
authors.affiliation: Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, India.|School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India.
authors.forename: B M
authors.initials: BM
authors.lastname: Shivakumar
authors.affiliation: School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India.
authors.forename: Sanjiban
authors.initials: S
authors.lastname: Chakrabarty
authors.affiliation: School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India.
authors.forename: Harish
authors.initials: H
authors.lastname: Rotti
authors.affiliation: School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India.
authors.forename: Venu
authors.initials: V
authors.lastname: Seenappa
authors.affiliation: Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rao
authors.affiliation: Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Geetha
authors.affiliation: Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Mangalore, India.
authors.forename: B V
authors.initials: BV
authors.lastname: Tantry
authors.affiliation: Department of Pathology, Kasturba Medical College, Manipal University, Mangalore, India.
authors.forename: Hema
authors.initials: H
authors.lastname: Kini
authors.affiliation: Dharamsi Hospital, Chandni Chowk, Sangli, Maharashtra, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Dharamsi
authors.affiliation: Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: C Ganesh
authors.initials: CG
authors.lastname: Pai
authors.affiliation: School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India. ksatyamoorthy@manipal.edu.
authors.forename: Kapaettu
authors.initials: K
authors.lastname: Satyamoorthy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; C527677:FNDC3A protein, human; D005353:Fibronectins; C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Colorectal cancer; Copy number variations; IHC; Quantitative RT-PCR; Ulcerative colitis; aCGH