Virtual Library

Start Your Search

F. Skoulidis

Author of

  • +

    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • +

      MO15.02 - Impact of co-occurring genetic events on the signaling landscape of KRAS-mutant lung adenocarcinoma. (ID 2936)

      16:15 - 17:45  |  Author(s): F. Skoulidis

      • Abstract
      • Presentation
      • Slides

      Personalized medicine frameworks centered on identification and therapeutic targeting of dominant oncogenic driver mutations are rapidly becoming a standard of care in the clinical management of patients with lung adenocarcinoma. However, little is currently known about the nature and impact of co-occurring genetic events on signaling output downstream of initiating oncogenes. This lacuna in our understanding is particularly pertinent for the subgroup of KRAS-driven tumors, where mounting data point towards considerable heterogeneity in pathway activation and clinical response to targeted therapies. Here, we report a comprehensive analysis of genetic events that co-occur with or are mutually exclusive of mutant KRAS in a cohort of 230 lung adenocarcinomas and assess the impact of individual co-mutations on signaling streams using data derived from state of the art transcriptomic and (phospho)proteomic profiling of primary tumors.

      An integrated analysis of 230 lung adenocarcinomas from The Cancer Genome Atlas (TCGA) consortium was performed using mutation (whole exome sequencing), transcriptomic (RNASeq), and proteomic (reverse phase protein array) datasets. Fischer’s exact test was applied to identify secondary mutations that occurred more frequently in either KRAS-mutant (n=68) or KRAS-wild-type (n=162) tumors and (phospho)protein markers that associated with each co-mutation. Genes with a mutation rate of ≥3% in the overall cohort were included in the analysis.

      Mutations in 18 genes were associated with KRAS mutational status in patient tumors (p≤0.01). Mutations in EGFR (p=0.0001), NF1 (p=0.001), and TP53 (p=0.001) were negatively correlated with the KRAS mutation. On the other hand, mutations in STK11 were significantly more frequent in the KRAS-mutant cohort (p=0.004), as were mutations in ATM (p=0.023) and MTOR (p=0.045). The most significant positive association involved mutations in ARHGEF11, a gene that encodes a Rho guanine nucleotide exchange factor (p=0.0004). Mutations in STK11 (29.4%) and TP53 (29.4%), the two most highly prevalent genetic events within the KRAS-mutant cohort were mutually exclusive. Unsupervised hierarchical clustering of transcriptomic and quantitative (phospho)proteomic profiles revealed separation of STK11-mutant tumors at the first branch of the cluster dendrogram, indicating activation of distinct signaling pathways downstream of this key tumor suppressor gene. Several less frequent genetic events had prominent and consistent effects on signaling output. We focused our attention on signaling via the MAPK pathway which may impact clinical sensitivity to MEK inhibitors, one of the most promising classes of targeted agents currently in clinical development for KRAS-mutant tumors. Preliminary analysis suggests that mutations in 3 individual genes can identify a subgroup of tumors (19% of the cohort) with profoundly suppressed MAPK signaling flux.

      Analysis of recurrent secondary genetic events may define distinct and clinically relevant subsets of KRAS-mutant lung adenocarcinoma. Efforts to refine the sub-classification further and assess the impact of co-mutations on sensitivity to molecularly targeted agents are underway and updated results will be presented at the meeting.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.