Mutational analysis of EGFR signaling pathway genes in lung adenocarcinomas
7584 Background: About fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode signaling proteins in the EGFR signaling pathway, i.e. EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other somatic mutations that could contribute to lung tumorigenesis. Methods: We analyzed genomic DNA from 261 resected, clinically well-annotated non-small cell lung cancer (NSCLC) specimens. 90% of tumors were adenocarcinomas, and 10% were squamous cell carcinomas. The coding sequences of 39 genes, encoding proteins mostly in the EGFR signaling cascade and FGFR1–4, were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Results: First-pass analysis of 9 MB of tumor sequence identified 199 distinct types of genetic variants that differed from published reference sequences. At least one variant was found in each gene analyzed. In addition to 6 variants found in RAS genes, we further examined the 94 variants localized to exons encoding the kinase domain of respective proteins. We have thus far identified known somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, in addition to a number of previously unreported single nucleotide polymorphisms (SNPs). Conclusions: Mutational profiling of genes that encode for components of the EGFR signaling pathway has revealed multiple putative genetic variants in lung adenocarcinomas. Further analysis of potential somatic mutations is in progress. No significant financial relationships to disclose.