Comprehensive analysis of tumor NGS data to demonstrate pathways pointing to therapeutic targeting options

Autor: Rachana Sainger, William H. Biggs, Ramlah Nehring, Alex Thomas, Brad A. Perkins, Ezra E.W. Cohen, Boyko Kakaradov, Alexandra E Gylfe, Kimberly Pelak, Ally Perlina, Thanemozhi G. Natarajan, Heather L Smith, Eve Shinbrot, Wayne Delport, Corine K. Lau, Subha Krishnan, Kenneth Joel Bloom
Rok vydání: 2017
Předmět:
Zdroj: Journal of Clinical Oncology. 35:e23153-e23153
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2017.35.15_suppl.e23153
Popis: e23153 Background: Recent advancements in NGS technology have enabled precision medicine based on tumor-specific genomic alterations. However, the complex nature of tumor biology demands an integrative analysis of genomic variations to identify converging downstream targets potentially regulated by multiple pathways. Methods: Genomic alterations from whole-genome sequencing results were interpreted in the context of pathways. Beyond listing the implicated known pathways based on genomic alterations, we explored protein interactions cross-linking the pathways to converging downstream targets. An in-house analytical pipeline was used to prioritize candidate pathways from MetaBase™, which contains manually curated pathways and interactions based on published experimental results. Custom pathway diagram was then designed manually to depict the most actionable pathways. The manual review consists of context-checking and addressing the concordant/discordant nature of all interactions. Factor such as mutational impact, directionality, mechanism of interaction and known targeted action are taken into account. Results: Comprehensive analysis of the genomic variations in three tumors types revealed activation of multiple oncogenic signaling pathways. Key events driving the tumor in a melanoma sample were NF1/RAS/MEK/ERK, WNT/beta-catenin pathway, and MITF signaling. Three interconnected signaling pathways, WNT, PI3K/AKT, and P53 were impacted by genomic alterations in a colorectal sample, which point to activation of converging downstream targets- CDK6, VEGFA, and COX-2. Integrated discovery of genomic alterations in an esophageal adenocarcinoma sample suggested potential activation of PI3K/AKT/MTOR and p16/Cyclin D1/CDK pathways. This could synergistically activate downstream converging targets- VEGFA, Cyclin D1, CDK6, CDK4, AURKA; some of which also showed relative RNA overexpression, supporting our pathway findings. Conclusions: Comprehensively analyzing the genomic alterations in context of cell signaling pathways provides us insights on how the pathways synergistically affect downstream targetable events, which in turn can impact therapeutic decisions.
Databáze: OpenAIRE
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