Abstract
<div>Abstract<p>There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic <i>BRAF</i> variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver <i>EGFR</i> mutations. <i>KRAS</i> mutations were present in AAHs from 4 of 22 (18%) of patients. <i>KRAS</i> mutations in AAH were only found in ever-smokers and were exclusive to <i>BRAF</i>-mutant cases. Integrative analysis revealed profiles expressed in <i>KRAS</i>-mutant cases (<i>UBE2C, REL</i>) and <i>BRAF</i>-mutant cases (<i>MAX</i>) of AAH, or common to both sets of cases (suppressed <i>AXL</i>). Gene sets associated with suppressed antitumor (Th1; <i>IL12A, GZMB</i>) and elevated protumor (<i>CCR2, CTLA-4</i>) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent <i>BRAF</i> or <i>KRAS</i> pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. <i>Cancer Res; 77(22); 6119–30. ©2017 AACR</i>.</p></div>
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