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Clinico-Pathological Association of Delineated miRNAs in Uveal Melanoma with Monosomy 3/Disomy 3 Chromosomal Aberrations

Author

Listed:
  • Nalini Venkatesan
  • Jagat Kanwar
  • Perinkulam Ravi Deepa
  • Vikas Khetan
  • Tamsyn M Crowley
  • Rajeswari Raguraman
  • Ganesan Sugneswari
  • Pukhraj Rishi
  • Viswanathan Natarajan
  • Jyotirmay Biswas
  • Subramanian Krishnakumar

Abstract

Purpose: 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. Conclusion: 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.

Suggested Citation

  • Nalini Venkatesan & Jagat Kanwar & Perinkulam Ravi Deepa & Vikas Khetan & Tamsyn M Crowley & Rajeswari Raguraman & Ganesan Sugneswari & Pukhraj Rishi & Viswanathan Natarajan & Jyotirmay Biswas & Subra, 2016. "Clinico-Pathological Association of Delineated miRNAs in Uveal Melanoma with Monosomy 3/Disomy 3 Chromosomal Aberrations," PLOS ONE, Public Library of Science, vol. 11(1), pages 1-14, January.
    • Handle: RePEc:plo:pone00:0146128
    DOI: 10.1371/journal.pone.0146128
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