Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard of care therapy, 14.4% (69/478) received matched therapy with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of pre-existent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers.

mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of mutations, patients with-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with -mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. We identified patients with advanced -mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Among 330 patients with advanced -mutant lung cancers, the most frequent co-mutations were found in (42%), (29%), and/ (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in / [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; ≤ 0.001]. (HR, 1.3; = 0.22) and (HR 1.11, = 0.58) co-mutation statuses were not associated with survival. Co-mutation in/ was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; = 0.003). Among people with -mutant advanced NSCLC,, and / are the most commonly co-occurring somatic genomic alterations. Co-mutation of and/ is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy..

Background Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to TGF beta signaling, including bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1), endoglin (ENG), and mothers against decapentaplegic 9 (SMAD9). Approximately 25% of heritable cases lack identifiable mutations in any of these genes. Methods and Results We used whole exome sequencing to study a three generation family with multiple affected family members with PAH but no identifiable TGF beta mutation. We identified a frameshift mutation in Caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries. Conclusions Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology as well as PAH-directed therapeutic development.

To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled -mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing. Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic -mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by and studies. In 200 -mutant pretreatment samples, the most frequent concurrent alterations were mutations in, and and focal amplifications in, and Shorter time to progression on EGFR TKI was associated with amplification of (HR = 2.4, = 0.015) or (HR = 3.7, = 0.019), or mutation in (HR = 1.7, = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), (7%), and amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included fusion, fusion, amplification, loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI and -mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally..