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Z. Barabash
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-041 - Identification of the Functional Significance of Mutations in Lung Cancer Using the Novel Precision Cancer Analysis System (ID 1000)
09:30 - 09:30 | Author(s): Z. Barabash
- Abstract
Background:
Mounting evidence indicates that growth of pathologically identical lung cancers in each individual patient is fueled by different sets of driving mutations. The need to identify these drivers stems from the recognized necessity for tailoring therapy and scheduling future surveillance. This personalized medical approach has been shown to result in better treatment outcomes. We present a novel Precision Cancer Analysis system (PCAS) capable of identifying activated signaling pathways by means of a transfected cell-based fluorescent reporter assay yielding a quantitative output of particular pathway activation levels. Being a functional platform PCAS reveals activated pathways regardless of the type of mutation behind it, i.e. whether it is already a known mutation or a variant of unknown significance (VOUS) mutation.
Methods:
In 10 patients with lung cancer next generation sequencing (NGS) was employed to sequence a set of 37 genes relevant in lung carcinogenesis. These genes were sequenced with 90 -100 % coverage. According to the prevalence of mutations in the analyzed cohort 3 major genes were selected for the current study: EGFR, PIK3CA and KRAS. These genes were then mapped to their major signaling pathways, and the reporters that best account for their activation were selected. Four major signaling pathways were found to be relevant for these genes‐ MAPK, STAT, NFkB and AKT.
Results:
In analyzed samples of 10 patients 14 mutations were identified, among them 3 in the tested genes: 2 in KRAS and 1 complex mutation in EGFR. The remaining mutations were found in STK11, CDKN2A, NF1, RB1 and TP53 genes. Of mutations found in KRAS 1 was known mutation (K117N) and 1 was VOUS (G60R). The former caused activation via MAPK/ERK but not via AKT pathway. The latter, never so far reported in cancer, significantly activated both pathways: MAPK/ERK and AKT. Interestingly the VOUS KRAS mutation was identified in carcinoid, whereas 2 carcinoid samples from other individuals displayed no mutations in the 37-gene panel. Additionally, 1 VOUS in RB1 and 2 mutations in STK11 were found to be associated with cancer cells aggressiveness evidenced by vessel and nerve tissue invasion. Measuring the functional mechanism behind known mutations and VOUS provides another layer of critical information to the physician.
Conclusion:
The study produced a comprehensive delineation of the oncogenic activity of each patients’ individual mutations demonstrating the ability of the PCAS to: Accurately deliver comparable actionable information as found by NGS Functionally characterize mutations annotated as VOUS. Monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions.
