Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Abstract

Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood.Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n ¼ 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups.Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies 60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of neversmokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma.Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. Clin Cancer Res; 20(18); 4912-24. Ó2014 AACR.

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

“…Combined with similar findings of intrinsically heterogeneous gene expression and CNA patterns in smoking-defined adenocarcinoma subgroups (20,31), our results question whether never-smokers can be identified as a molecular subgroup of its own with transcriptional, DNA methylation, and CNA patterns clearly different from tumors arising in smokers. Instead, our study further supports that a majority of adenocarcinomas arising in never-smokers together with a specific subset of tumors from smokers represent a more distinct and relevant molecular/biologic entity of less aggressive and potentially more smoking-unrelated disease (20,31). The clinical smoking definitions are intrinsically problematic due to their self-reported nature, but also because they do not capture the intensity and duration of cigarette exposure, and the exposure to environmental tobacco smoke and other pollutants for never-smokers.…”

“…The TCGA consensus clusters were derived by unsupervised consensus clustering of the most varying genes (SD of variation across tumors >1) using a three-group solution as described in ref. (31). P values were calculated using the c 2 test.…”

“…(31). This analysis identified seven genes with false discovery rate 10%, including four well-known tumor suppressor genes (KEAP1, TP53, STK11, and SMARCA4) and three genes appearing as either false positives (COL11A1, and LRRIQ3), or with <10% mutation frequency in any epitype (SNRPN).…”

Identification of feature genes for smoking-related lung adenocarcinoma based on gene expression profile data

“…A recent study by Vucic et al9 found that microRNAs disrupted in a smoking status-dependent manner affected distinct cellular pathways and differentially influenced lung cancer patient prognosis in current, former, and never smokers. Moreover, Karlsson et al10 identified some genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history. In spite of these findings, we think it is not enough in the clinical practice.…”

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

“…In recent years, the genomic landscape of NSCLC has been extensively investigated (2)(3)(4). However, for the majority of NSCLC patients, treatment options are still limited, and the overall prognosis remains poor.…”