Data from Clinical and Molecular Characteristics of <i>NF1</i>-Mutant Lung Cancer

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt;&lt;i&gt;NF1&lt;/i&gt; is a tumor suppressor that negatively regulates Ras signaling. &lt;i&gt;NF1&lt;/i&gt; mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of &lt;i&gt;NF1&lt;/i&gt; mutant lung cancers with comparison to tumors with &lt;i&gt;KRAS&lt;/i&gt; mutations.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Between July 2013 and October 2014, 591 non–small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. &lt;i&gt;NF1&lt;/i&gt; and &lt;i&gt;KRAS&lt;/i&gt; cohorts were identified, with subsequent clinical and genomic analysis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Among 591 patients, 60 had &lt;i&gt;NF1&lt;/i&gt; mutations (10%) and 141 (24%) had &lt;i&gt;KRAS&lt;/i&gt; mutations. 15 &lt;i&gt;NF1&lt;/i&gt; mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique &lt;i&gt;NF1&lt;/i&gt; variants. &lt;i&gt;NF1&lt;/i&gt; tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, &lt;i&gt;KRAS&lt;/i&gt; mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among &lt;i&gt;NF1&lt;/i&gt; tumors without concurrent oncogenic alterations, &lt;i&gt;TP53&lt;/i&gt; mutations/2-copy deletions occurred more often (33, 65%) than with &lt;i&gt;KRAS&lt;/i&gt; mutation (46, 35%; &lt;i&gt;P&lt;/i&gt; &lt; 0.001). No difference between cohorts was seen with other tumor suppressors.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt;&lt;i&gt;NF1&lt;/i&gt; mutations define a unique population of NSCLC. &lt;i&gt;NF1&lt;/i&gt; and &lt;i&gt;KRAS&lt;/i&gt; mutations present in similar patient populations, but &lt;i&gt;NF1&lt;/i&gt; mutations occur more often with other oncogenic alterations and &lt;i&gt;TP53&lt;/i&gt; mutations. Therapeutic strategies targeting &lt;i&gt;KRAS&lt;/i&gt; activation, including inhibitors of MAP kinase signaling, may warrant investigation in &lt;i&gt;NF1&lt;/i&gt; mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. &lt;i&gt;Clin Cancer Res; 22(13); 3148–56. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;