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W.W. Lockwood

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.09 - Amplification of YEATS4, a novel oncogene in NSCLC, inhibits the p53 pathway and increases resistance to cisplatin (ID 1073)

      16:15 - 17:45  |  Author(s): W.W. Lockwood

      • Abstract
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      • Slides

      Characterization of lung cancer genomes has revealed a number of genes critical to tumorigenesis (e.g. EGFR, KRAS, EML4-ALK), resulting in significant changes to the treatment of lung cancer and an increase in survival for a subset of patients. These successes have prompted the search for additional driver alterations, leading to the discovery of a number of recurrently mutated or amplified genes and gene fusions with promising clinical utility. Distinguishing the key mechanisms and causal events driving tumorigenesis will lead not only to a better understanding of lung cancer phenotypes and biology, but also to new molecular markers and therapeutic targets. Using an integrative analysis of gene expression and copy number data to identify novel candidate oncogenes, we identified the chromosomal region at 12q13-15, and more specifically, the putative transcription factor YEATS4 (YEATS domain containing 4) as frequently amplified and overexpressed in NSCLC. Amplification of YEATS4 has been reported in dedifferentiated liposarcomas and in the earliest stages of glioma and astrocytoma.

      Copy number profiles were generated for 261 NSCLC tumors (169 adenocarcinomas (AC) and 92 squamous cell carcinomas (SqCC)) and expression profiles for a subset of tumors with matched non-malignant tissue. Recurrent DNA amplifications were identified using the GISTIC algorithm. Copy number data were integrated with gene expression data to identify genes frequently amplified and overexpressed (defined as a 2-fold difference in expression between tumor and matched non-malignant tissue). The functional significance of YEATS4 was assessed by lentiviral knockdown in lung cancer cell lines with and without YEATS4 amplification and ectopic expression in human bronchial epithelial cells (HBECs). In vitro and in vivo assays measuring proliferation, anchorage independent growth, senescence, apoptosis, drug sensitivity and tumor growth were used to assess the phenotypic effect of YEATS4 gene expression manipulation.

      YEATS4 is gained or amplified and concomitantly overexpressed in over 20% of NSCLC tumors, with similar frequencies of amplification in both AC and SqCC. Although frequently co-amplified with MDM2, amplification of YEATS4 was observed to occur in the absence of MDM2 amplification, suggesting it is not merely a passenger event. Overexpression of YEATS4 in HBECs abrogated senescence, whereas knockdown reduced cell proliferation, impaired colony formation and induced cellular senescence in cell lines with YEATS4 amplification. Western blotting revealed increased p21, cleaved PARP and p53 in knockdown lines compared to empty vector controls, implicating YEATS4 as a negative regulator of the p21-p53 pathway. Moreover, YEAST4 expression was found to correlate with cisplatin sensitivity, as overexpression increased resistance and knockdown conferred sensitivity. Consistent with our in vitro findings, tumor size and growth were significantly reduced in mice injected with YEATS4 knockdown cells relative to control mice. Furthermore, survival analysis revealed that patients expressing high levels of YEATS display poorer outcomes.

      Our findings reveal YEATS4 as a novel candidate oncogene frequently amplified and overexpressed in NSCLC. Gene expression manipulation resulted in distinct phenotypic changes consistent with oncogenic function, and suggesting YEATS4 amplification is a novel mechanism contributing to NSCLC tumorigenesis.

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