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Katherine D. Lach



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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.09 - Differential Gene Expression in Tumor and Normal Tissue Reveals New Insights in the Biology of Non-Small Cell Lung Carcinoma. (ID 13341)

      16:15 - 16:20  |  Author(s): Katherine D. Lach

      • Abstract
      • Presentation
      • Slides

      Background

      Effective use of targeted cancer therapies typically depends upon the identification of actionable genomics somatic alterations, benefiting only a minority of Non-Small Cell Lung Carcinoma (NSCLC) patients. To integrate transcriptomic assessment in cancer precision medicine, we have evaluated the mRNA expression levels in tumors and their matched normal lung tissues with the hypothesis that mRNA quantification in tumors relative to their matched normal tissue may better reveal small transcriptional differences that are associated with major biological effects.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The discovery set used 123 frozen macrodissected treament-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Mutualiste Montsouris Institute (Paris, France), and the validation set used 143 FFPE macrodissected treatment-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Jewish General Hospital (Montreal, QC, Canada). A pathology review was performed in all cases. In the discovery set, expression levels of 17,318 genes were analysed using an Agilent Technologies platform; in the validation set, the NanoString nCoutner technology was used with a customized 148 probeset that was designed according to the results of the discovery phase. The primary objective of the study was post-surgery progression-free survival (PFS). The secondary objectives were post-surgery overall survival (OS) and the identification of pathway-driven expression signatures.

      4c3880bb027f159e801041b1021e88e8 Result

      A set of highly expressed genes correlated with post-surgery PFS. Details of the prognostic signature will be presented at the meeting. Importantly, mRNA levels in normal tissues were highly variable between individuals. Organ matched reference enabled to control for the noise signals related to individual background genetic variability. The cell cycle G2/M checkpoint was the most significantly deregulated expression pathway in this cohort; nine genes in the signature are involved in this pathway and were upregulated in tumors, dependending on their histology: CHEK1, TOP2A, AURKA, CDC2, PLK1, CDC2, CDC25A, CDC25B, and CDC25C. CHEK1 is a pivotal gene in regulating the G2/M cell cycle pathway that triggers the double-strand base excision repair in which the main effector is PARP1. CHEK1 was overexpressed in 86% of adenocarcinomas, versus 42% for PARP1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conventional transcriptomic approaches using expression metrics obtained in tumor pools may miss important changes due to individual variability in non-tumoral tissue.The present work illustrates that paired matched tumor and normal tissues can identify new key genes involved in the biology and pathogenesis of NSCLC, and opens new avenues for integrating transcriptomic investigations in the precision medicine arena.

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