Abstract Oncogenomic mutations found in NSCLC are potential therapeutic targets, as seen in the dramatic responses individuals with EGFR mutations have to tyrosine kinase inhibitors. Somatic mutations in tumors of the lung are being rapidly identified, with mutational profiles often correlating with clinical features and smoking history. There are likely novel mutations yet to be identified that may serve as future therapeutic targets, or may help distinguish between sub-types of lung cancer. We selected 58 patients with either BAC (n=9), adenocarcinoma, NOS (AC) (n=22), or squamous cell carcinoma (SCC) (n=27) from previous population-based studies of lung cancer. Women comprised 70.7% of the study population, and 32.8% reported never smoking. Tumor DNA was extracted from formalin fixed paraffin embedded tissue. We examined 238 mutations in 19 common oncogenes using the OncoCarta Assay v1.0 (Sequenom). We identified a total of 26 mutations in tumors from 21 individuals; the remaining 37 tumors did not have mutations. Mutations were identified in EGFR (n=13), KRAS (n=6), PIK3CA (n=5), PDGFRA (n=2) and CDK1 (n=1). Tumors from 5 individuals had simultaneous mutations in 2 or 3 genes. Specifically, 2/5 PIK3CA mutations occurred in tumors with EGFR mutations and 2/6 KRAS mutations also had a PIK3CA or a PDGFRA mutation. In addition, one tumor was mutated in EGFR, CDK1 and PDGFRA. EGFR mutations consisted of 8 in-frame micro-deletions in exon 19 (amino acids 746-750), 3 in exon 20 (L858R) and 1 in exon 19 (G719S). KRAS mutations were all in amino acid 12. PIK3CA mutations consisted of E542K, E545K, E547K, M1043I and H1047R. We tested for association of the detected mutations with one another as well as with several environmental and clinical features. There was a significant association of EGFR and PIK3CA mutations in tumors that had a mutation in either gene (p=0.043, Fisher's test). It is noteworthy that resistance to EGFR tyrosine kinase inhibitors has been shown to occur through PIK3CA activating mutations. Consistent with previous studies, EGFR mutation was more likely to occur in non-smokers (p=1.8E-05 Fisher's test) and the significance of this effect was more pronounced when analyzed against the number of pack years smoked (p=5.3E-05, Kruskal-Wallis test). Whereas the number of pack years smoked associated significantly with chronic obstructive pulmonary disease (COPD) (p=0.0064, Kruskal-Wallis test), no association was found with any mutation and COPD status. With respect to lung cancer subtype, EGFR mutation was strongly associated with the BAC subtype (p=0.0025, Fisher's test). Indeed, 6/9 BAC tumors exhibited an EGFR mutation. Of the 6 KRAS mutations identified, two BAC tumors from smokers carried the G12C and G12D mutations, respectively. Two non-smoking individuals (1 AC, 1 BAC) had KRAS mutations and each harbored an additional mutation (KRAS G12A / PDGFR-alpha D842V and KRAS G12D / PIK3CA E545K, respectively). Data from 90 additional samples will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2228.