Mutational profiling of the oncogenome in non-small cell lung cancer (NSCLC).

7021 Background: Cancers arise from a multistage process during which tumor cells acquire activating mutations in proto-oncogenes and inactivating mutations in tumor suppressor genes. In NSCLC, somatic mutations have been detected in genes such as EGFR, HER2, PIK3CA, BRAF, KRAS, and p53. Two of these mutations are now known to have direct clinical relevance; mutations in the EGFR tyrosine kinase domain are associated with tumor responses to targeted therapies such as gefitinib and erlotinib (Lynch et al, NEJM '04, Paez et al, Science '04, Pao et al, PNAS '04), while KRAS mutations are found in tumors refractory to these agents (Pao et al, PLoS Med '05). Moreover, EGFR and KRAS mutations are mutually exclusive (Shigematsu et al, JNCI '04). To identify new predictors of response as well as novel targets for therapy, we have initiated a comprehensive large-scale re-sequencing analysis of genes potentially mutated in NSCLC, i.e. the NSCLC oncogenome.,Genomic DNA was extracted from 188 early-stage resected untreated NSCLCs. All tumors were obtained on IRB-approved protocols and with patients' consent. High-throughput PCR-based re-sequencing was performed on a high priority list of ∼100 genes, with particular focus on genes in the ERBB signaling pathway.,Thus far, 110 tumors have been analyzed for EGFR (exons 2-28) and KRAS2 (exons 1-6) mutations. 11 tumors (10%) had EGFR mutations (exons 19 and 21), while 19 (17%) had KRAS mutations (exon 2). EGFR and KRAS mutations were mutually exclusive. No mutations were identified among 11 never smokers analyzed for changes in FLT3 (exons 2-24).,Mutational profiling of NSCLC can distinguish clinically relevant molecular subsets of lung cancer, and may reveal novel targets for therapy. Further re-sequencing of the NSCLC oncogenome is in progress. [Table: see text].