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Jhon Ralph Enterina

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-050 - Pan-Can Analysis of miRNAs at the Imprinted Chromosome 14q32 Locus Reveals a Unique Pattern of Deregulation in NSCLC (ID 9116)

      09:30 - 16:00  |  Presenting Author(s): Jhon Ralph Enterina

      • Abstract

      Genes expressed at the imprinted chromosome 14q32 locus play crucial roles in both fetal and adult development. The protein-coding genes expressed by the paternal allele are required for proper placentation and organogenesis; while the expression of non-coding genes encoded by the maternal allele were found to be temporally active in the brain. Previous reports identified few miRNAs at the locus that were able to stratify low and high risk patients with non-small cell lung carcinoma (NSCLC). However, a locus-wide analysis of miRNA deregulation across smoking-associated tumours still remains unexplored. To address this, we quantified the expression of 51 miRNAs in 10 smoking-associated cancer types and assessed their differential expression in unpaired normal and malignant tissues.

      We analyzed the small RNA transcriptome in 10 cancer types from The Cancer Genome Atlas (TCGA) clinical cohorts (i.e. LUAD, LUSC, HNSC, kidney, stomach, esophagous, bladder, cervical, pancreas and liver). All small RNA sequencing reads were aligned on the human genome build 19 (hg19) and normalized using our in-house bioinformatics pipeline. miRNAs with expressions greater than or equal to 1.0 RPM in 10 percent of samples were included for further analysis. Zeta-score values were calculated and used for unsupervised hierarchical clustering to identify distinct patterns of deregulation across different cancer types. We validated our findings using 132 paired NSCLC samples from the British Columbia Cancer Agency (BCCA). Small RNA sequencing of the validation cohort was performed using Illumina Hi-seq 2000 platform. All samples were microdissected prior to RNA isolation.

      We identified 39 miRNAs that are expressed in all cancer types included in this study. Unsupervised hierarchical clustering based on miRNA z-score values revealed a distinct pattern of deregulation in NSCLC compared to other smoking-associated malignancies. Many of these miRNAs were upregulated in both lung adenocarcinoma and squamous carcinoma while other cancers showed either repression or unchanged expression. We further assessed the expression of these miRNAs in metastatic (with lymph node/distant organ invasion) and non-metastatic lung adenocarcinoma (LUAD) cases using TCGA and BCCA clinical cohorts. From this analysis, we found miR-323b, miR-433 and miR-889 consistently unregulated (p value ≤ 0.01) in metastatic tumours.

      NSCLC tumours showed a unique pattern of deregulation in chromosome 14q32 small non-coding genes when compared with other smoking-associated malignancies. Also, we identified three miRNAs that were significantly upregulated in metastatic LUAD cases. Target prediction and thorough functional assays of these miRNAs may reveal novel pathways disrupted during the metastatic progression of LUAD.