Author of

• 11543

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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11566

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    P2.06-023 - Gene expression signature and immunohistochemical assessment of NRF2 pathway activation for adjuvant chemotherapy benefit in lung squamous cell carcinoma (SqCC) (ID 1990)

    09:30 - 09:30  |  Author(s): C.Q. Zhu
    • Abstract

    Background
    Genomic profiling of SqCC has identified somatic alterations in NRF2 or its negative regulators (NFE2L2 mutations/amplifications, KEAP1 or CUL3 mutations/deletions) in ~1/3 of tumors. These alterations result in activation of the NRF2 transcriptional program, but the clinical significance of this pathway in lung SqCC patients is unknown. We hypothesize that a gene expression signature that reflects somatic NRF2-activating alterations may be identified and correlated with NRF2 protein over-expression. Furthermore, such gene expression or its immunohistochemical correlates may have prognostic significance and/or may be predictive of adjuvant chemotherapy benefit in early stage resectable lung SqCC patients.

    Methods
    Logistic regression (LR) and SAM analysis were applied independently to 104 SqCC cases from The Cancer Genome Atlas (TCGA) that had both microarray gene expression and mutation data to identify genes associated with NRF2 pathway mutational status. Overlapping genes were used to define the signature, which was then tested in 3 independent SqCC microarray datasets to evaluate its prognostic value. Correlation of the signature with NRF2 and KEAP1 mutations and with NRF2 and KEAP1 immunoreactive protein expression by immunohistochemistry (IHC) was evaluated. We also tested the gene expression signature as a potential predictor of adjuvant chemotherapy benefit in a subset of NCIC JBR.10 adjuvant chemotherapy trial patients with microarray data.

    Results
    A 28-gene signature that distinguished SqCC with or without aberration of the NRF2 pathway genes (NFE2L2/KEAP1/CUL3) in the TCGA dataset was identified. This gene signature that putatively represents NRF2 pathway activation status separates consistently SqCC into 2 groups in independent datasets. Both NRF2/KEAP1 mutation and NRF2 protein expression by IHC were significantly correlated with the NRF2 pathway activation signature (p<0.001 for each comparison). KEAP1 protein expression was not associated with the gene expression signature. No prognostic effect of the activated signature was observed in three independent datasets. In the JBR.10 patient cohort, a trend toward improved survival with adjuvant chemotherapy was observed in patients with the NRF2 “wild type” signature (HR 0.32, 95%CI 0.065-1.6 p=0.16), but not in patients with the “activated” signature (HR 2.28, 95%CI 0.24–22, p=0.48; interaction p=0.15).

    Conclusion
    A gene expression signature based on mutational activation of the NRF2 pathway may be predictive of benefit from adjuvant cisplatin/vinorelbine in SqCC. Patients with NRF2 pathway activating somatic alterations may have reduced benefit from this therapy. NRF2 immunohistochemistry could potentially be useful to identify NRF2-activated lung SqCC patients who may not benefit from adjuvant chemotherapy but this requires further validation.

• 12386

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  P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12394

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    P3.02-008 - TRIM14 is a Novel Tumor Suppressor Gene in Non-Small-Cell Lung Cancer (ID 1204)

    09:30 - 09:30  |  Author(s): C.Q. Zhu
    • Abstract

    Background
    Non-small-cell lung carcinoma (NSCLC) accounts for 85% of all malignant lung tumors. Our group previously identified Tripartite Motif-Containing 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC patients. TRIM14 belongs to a conserved family of Tripartite Motif-encoding genes involved in a broad range of biological processes, such as transcriptional regulation, cell proliferation, and apoptosis. However, TRIM14 itself is poorly understood. Here we investigate the functional and prognostic role of TRIM14 in NSCLC.

    Methods
    Cox proportional hazards regression analysis was done on published mRNA expression datasets of primary NSCLCs to identify whether TRIM14 expression is associated with patient survival. The expression of TRIM14 was modified in human NSCLC cell lines (NCI-H1395, NCI-H1650, NCI-H520 and NCI-H157) by lentivirus-mediated overexpression and short-hairpin RNA (shRNA)-mediated silencing. Effects were assessed by examining in vitro cell proliferation and anchorage-independent growth, and in vivo tumorigenicity in mice.

    Results
    Univariate analyses demonstrated that TRIM14 expression is significantly associated with patient survival, with loss of expression correlated with poorer prognosis in resectable early stage NSCLC patients. In vitro studies showed that TRIM14 overexpression in H1395 cells suppressed proliferation and anchorage-independent growth, whereas shRNA knockdown of TRIM14 expression in H1650, H520, and H157 cells promoted cell proliferation and colony formation. In vivo studies demonstrated that suppressing TRIM14 expression in H1650 and H157 cells significantly promotes tumor growth in immunodeficient mice.

    Conclusion
    We show that TRIM14 may function as a tumor suppressor gene in NSCLC affecting cell proliferation and anchorage-independent growth in vitro and tumor growth in mice. We provide evidence that prognostic genes identified in microarray based gene expression analyses may have a strong biological rationale.