Author of

• 18974

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  P3.02 - Biology/Pathology (ID 620)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24038

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    P3.02-090 - Hypoxia-Induced Modifications of the Small Non-Coding RNA Transcriptome Delineates Risk of Recurrence in Early-Stage Lung Adenocarcinoma (ID 8400)

    09:30 - 09:30  |  Author(s): N. Firmino
    • Abstract

    Background:
    Hypoxia is central to neoplastic diseases. It has been associated with reduced survival in several tumor types, including NSCLC. A spectrum of poor outcome suggests a multifactorial modulation of the hypoxic response. Piwi-interacting RNAs (piRNAs) are small non-coding RNAs (sncRNAs) with a pivotal role in genomic stability and epigenetic regulation of gene expression. Changes in piRNA expression have been recently found to be deregulated during tumor progression, and responsive to tumor microenvironment conditions. Here, we investigate if hypoxia alters the piRNA transcriptome in human lungs, and assessed whether these alterations are indicative of outcome in patients with hypoxic lung tumours.
    
    Method:
    Tumors from lung and other six organs (TCGA) were classified according to their oxygenation state using signatures derived from established hypoxia-associated gene expression changes. By investigating >3000 piRNA transcriptomes, we generated a baseline of hypoxia-related changes which were further validated in a panel of cell lines exposed to hypoxia in vitro (16h at 1% O~2~). In lung tumors (n=1,018), we identified the most robust hypoxia-related changes between hypoxic and non-hypoxic groups by including piRNAs that: 1) ≥ 10 RPKM median expression, 2) > 2-fold change in median expression, and 3) a significant p value following a Mann-Whitney U test. A piRNA-based score (piSco) was generated by grouping HR-piRNAs expression, weighted by coefficients from a Cox proportional hazard model.
    
    Result:
    Overall, piRNA expression is selectively deregulated by hypoxia. In vitro tumour models recapitulate HR-piRNAs expression patterns. Seventy-one HR-piRNAs were identified, showing statistically significant differences in expression between hypoxic and non-hypoxic tumours. Of these, 13 were exclusively deregulated in NSCLC tumors, showing a remarkable subtype specificity between adenocarcinomas and squamous cell carcinomas. We next investigated if the HR-piRNA based score (piSco) was associated with NSCLC patient outcome. We found that piSco classify patients with hypoxic lung LUAD and LUSC as low or high risk of RFS. Remarkably, piSco was also able to classify Stage I LUAD patients into the same categories above (p = 0.0051).
    
    Conclusion:
    This study reveals the influence of the tumour microenvironment on DNA-level regulatory mechanisms with important implications for predicting recurrence in patients with hypoxic lung tumours. Our data encourage further exploration of HR-piRNAs as clinical tools for evaluating the likelihood of tumour recurrence, and as a mean to identify patients that would most benefit from adjuvant therapies and/or therapies designed to target hypoxic tumour cells.