title: Clinico-Pathological Association of Delineated miRNAs in Uveal Melanoma with Monosomy 3/Disomy 3 Chromosomal Aberrations.
abstract: OBJECTIVE
  To correlate the differentially expressed miRNAs with clinico-pathological features in uveal melanoma (UM) tumors harbouring chromosomal 3 aberrations among South Asian Indian cohort.
  
  
  METHODS
  Based on chromosomal 3 aberration, UM (n = 86) were grouped into monosomy 3 (M3; n = 51) and disomy 3 (D3; n = 35) by chromogenic in-situ hybridisation (CISH). The clinico-pathological features were recorded. miRNA profiling was performed in formalin fixed paraffin embedded (FFPE) UM samples (n = 6) using Agilent, Human miRNA microarray, 8x15KV3 arrays. The association between miRNAs and clinico-pathological features were studied using univariate and multivariate analysis. miRNA-gene targets were predicted using Target-scan and MiRanda database. Significantly dys-regulated miRNAs were validated in FFPE UM (n = 86) and mRNAs were validated in frozen UM (n = 10) by qRT-PCR. Metastasis free-survival and miRNA expressions were analysed by Kaplen-Meier analysis in UM tissues (n = 52).
  
  
  RESULTS
  Unsupervised analysis revealed 585 differentially expressed miRNAs while supervised analysis demonstrated 82 miRNAs (FDR; Q = 0.0). Differential expression of 8 miRNAs: miR-214, miR-149*, miR-143, miR-146b, miR-199a, let7b, miR-1238 and miR-134 were studied. Gene target prediction revealed SMAD4, WISP1, HIPK1, HDAC8 and C-KIT as the post-transcriptional regulators of miR-146b, miR-199a, miR-1238 and miR-134. Five miRNAs (miR-214, miR146b, miR-143, miR-199a and miR-134) were found to be differentially expressed in M3/ D3 UM tumors. In UM patients with liver metastasis, miR-149* and miR-134 expressions were strongly correlated.
  
  
  CONCLUSIONS
  UM can be stratified using miRNAs from FFPE sections. miRNAs predicting liver metastasis and survival have been identified. Mechanistic linkage of de-regulated miRNA/mRNA expressions provide new insights on their role in UM progression and aggressiveness.
authors.affiliation: Larsen & Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.|Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani-333031, Rajasthan, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Deakin University, Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia.
authors.forename: Jagat
authors.initials: J
authors.lastname: Kanwar
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani-333031, Rajasthan, India.
authors.forename: Perinkulam Ravi
authors.initials: PR
authors.lastname: Deepa
authors.affiliation: Department of Vitreoretinal and Ocular Oncology, Medical Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Khetan
authors.affiliation: School of Medicine, Deakin University, and Australian Animal Health Laboratories, CSIRO, Australia.
authors.forename: Tamsyn M
authors.initials: TM
authors.lastname: Crowley
authors.affiliation: Larsen & Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Rajeswari
authors.initials: R
authors.lastname: Raguraman
authors.affiliation: Department of Vitreoretinal and Ocular Oncology, Medical Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Sugneswari
authors.affiliation: Department of Vitreoretinal and Ocular Oncology, Medical Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Pukhraj
authors.initials: P
authors.lastname: Rishi
authors.affiliation: Department of Bio-statistics, Medical Research Foundation, Sankara Nethralaya, 41, College road, Chennai-600006, India.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.affiliation: Larsen & Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Jyotirmay
authors.initials: J
authors.lastname: Biswas
authors.affiliation: Larsen & Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 18/41, College road, Chennai-600006, India.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnakumar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000150:complications / Q000235:genetics* / Q000401:mortality; D002893:Chromosomes, Human, Pair 3; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D017403:In Situ Hybridization; D007194:India; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000150:complications / Q000401:mortality / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009006:Monosomy; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding; D012333:RNA, Messenger / Q000378:metabolism; D014604:Uveal Neoplasms / Q000150:complications / Q000401:mortality / Q000473:pathology*; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger
references.citation: Cancer Res. 2009 Aug 15;69(16):6704-12
references.pmid: 19654291
references.citation: Pigment Cell Melanoma Res. 2013 Nov;26(6):886-99
references.pmid: 24034838
references.citation: Curr Opin Ophthalmol. 2014 May;25(3):234-9
references.pmid: 24713608
references.citation: Adv Drug Deliv Rev. 2015 Jan;81:75-93
references.pmid: 25220354
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19971-6
references.pmid: 18056805
references.citation: PLoS One. 2013;8(12):e83398
references.pmid: 24391761
references.citation: Invest Ophthalmol Vis Sci. 2010 Apr;51(4):1811-6
references.pmid: 19892878
references.citation: N Engl J Med. 2010 Dec 2;363(23):2191-9
references.pmid: 21083380
references.citation: Indian J Ophthalmol. 2014 Feb;62(2):158-62
references.pmid: 24618486
references.citation: Melanoma Res. 2008 Jun;18(3):184-90
references.pmid: 18477892
references.citation: Eye (Lond). 2012 Sep;26(9):1157-72
references.pmid: 22744385
references.citation: Sci China Life Sci. 2011 Apr;54(4):351-8
references.pmid: 21509659
references.citation: Cancer Res. 2004 Oct 15;64(20):7205-9
references.pmid: 15492234
references.citation: Acta Ophthalmol. 2012 Sep;90(6):534-9
references.pmid: 21114636
references.citation: Expert Rev Mol Diagn. 2010 Apr;10(3):297-308
references.pmid: 20370587
references.citation: Arch Ophthalmol. 2001 May;119(5):670-6
references.pmid: 11346394
references.citation: Mol Cell Biochem. 2011 Apr;350(1-2):207-13
references.pmid: 21197560
references.citation: PLoS One. 2012;7(4):e35295
references.pmid: 22545102
references.citation: Hepatology. 2009 Aug;50(2):490-9
references.pmid: 19472311
references.citation: Indian J Ophthalmol. 2004 Mar;52(1):41-4
references.pmid: 15132378
references.citation: Cell Stress Chaperones. 2005 Summer;10(2):86-103
references.pmid: 16038406
references.citation: Int J Cancer. 1993 Apr 22;54(1):37-43
references.pmid: 8478146
references.citation: Chin Med Sci J. 2006 Mar;21(1):33-5
references.pmid: 16615282
references.citation: RNA. 2007 Oct;13(10):1668-74
references.pmid: 17698639
references.citation: Genes Dev. 2002 Jan 1;16(1):46-57
references.pmid: 11782444
references.citation: Ecancermedicalscience. 2014 Mar 11;8:410
references.pmid: 24688598
references.citation: Cancer Cell. 2011 Dec 13;20(6):741-54
references.pmid: 22172720
references.citation: PLoS Curr. 2013 Apr 09;5:null
references.pmid: 23591547
references.citation: Invest Ophthalmol Vis Sci. 2001 Feb;42(2):313-7
references.pmid: 11157859
references.citation: Am J Pathol. 2000 Dec;157(6):1795-801
references.pmid: 11106551
references.citation: Oncogene. 2003 May 15;22(19):2972-83
references.pmid: 12771949
references.citation: Invest Ophthalmol Vis Sci. 2009 Feb;50(2):500-4
references.pmid: 18824727
references.citation: Tumori. 2014 Jan-Feb;100(1):e4-7
references.pmid: 24675509
references.citation: Cancer Lett. 2009 May 8;277(1):8-21
references.pmid: 18824292
references.citation: Invest Ophthalmol Vis Sci. 2010 May;51(5):2329-37
references.pmid: 20042655
references.citation: J Biol Chem. 2012 Oct 12;287(42):34970-8
references.pmid: 22927443
references.citation: Cell Cycle. 2013 Jun 15;12(12):1879-91
references.pmid: 23676219
references.citation: Mol Vis. 2009;15:2146-54
references.pmid: 19898689
references.citation: Cancer Res. 2008 Jan 15;68(2):425-33
references.pmid: 18199536
references.citation: Int J Cancer. 2014 Feb 15;134(4):811-21
references.pmid: 23824713
references.citation: Acta Ophthalmol. 2014 Sep;92(6):541-9
references.pmid: 24373459
references.citation: Methods Mol Biol. 2014;1102:427-40
references.pmid: 24258991
references.citation: JAMA Ophthalmol. 2015 Sep;133(9):1073-6
references.pmid: 26086628
references.citation: Invest Ophthalmol Vis Sci. 2015 Mar;56(3):1447-58
references.pmid: 25593028