Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma
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American Association for Cancer Research Inc.
Abstract
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 BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. ©2017 AACR.
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Adenocarcinoma, Aged, Disease progression, Female, Gene expression profiling, Genomics, Humans, Hyperplasia, Lung, Lung neoplasms, Male, Middle aged, Mutation, Precancerous conditions, Proto-oncogene proteins b-raf, Proto-oncogene proteins p21(ras), B raf kinase, Chemokine receptor ccr2, Cytotoxic t lymphocyte antigen 4, Epidermal growth factor receptor, Granzyme b, Interleukin 12p35, K ras protein, Max protein, Oncoprotein, Transcription factor rel, Tyrosine kinase receptor, Tyrosine kinase receptor axl, Ube2c protein, Unclassified drug, Braf protein, human, Kras protein, human, Protein p21, Adenoma, Adult, Article, Clinical article, Controlled study, Disease course, Dna sequence, Gene expression, Genetic association, Genetic variability, Genome analysis, Human, Human cell, Human tissue, Immune response, Immunopathogenesis, Lung adenocarcinoma, Lung parenchyma, Oncogene, Oncogene braf, Oncogene k ras, Priority journal, Rna sequence, Signal transduction, Smoking, Somatic mutation, Th1 cell, Very elderly, Young adult, Disease exacerbation, Genetics, Lung tumor, Metabolism, Pathology, Precancer