Dataset Information

Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

ABSTRACT: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS.The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs.A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n?=?128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n?=?198) and for replication assay in another independent cohort (n?=?153).We identified SNPs at 4q12 associated with PFS at genome-wide significance (P?

SUBMITTER: Chang IS

PROVIDER: S-EPMC5363976 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

Chang I-Shou IS Jiang Shih Sheng SS Yang James Chih-Hsin JC Su Wu-Chou WC Chien Li-Hsin LH Hsiao Chin-Fu CF Lee Jih-Hsiang JH Chen Chih-Yi CY Chen Chung-Hsing CH Chang Gee-Chen GC Wang Zhaoming Z Lo Fang-Yi FY Chen Kuan-Yu KY Wang Wen-Chang WC Chen Yuh-Min YM Huang Ming-Shyan MS Tsai Ying-Huang YH Su Yu-Chun YC Hsieh Wan-Shan WS Shih Wen-Chi WC Shieh Shwn-Huey SH Yang Tsung-Ying TY Lan Qing Q Rothman Nathaniel N Chen Chien-Jen CJ Chanock Stephen J SJ Yang Pan-Chyr PC Hsiung Chao A CA

American journal of respiratory and critical care medicine 20170301 5

<h4>Rationale</h4>Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS.<h4>Objectives</h4>The aim of this study was to ...[more]

PMID: 27669169

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Project description:Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change>1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p=0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers. Experiment Overall Design: Overall, 180 adenocarcinoma and non-tumor tissue samples were selected for the analyses, including duplicate or triplicate samples from 14 subjects for quality control. From the original 180 samples, 148 provided sufficient quantity of high-quality RNA for microarray analyses; 13 additional samples were excluded because of problematic assays. Normalization was conducted on the remaining 135 microarrays. After normalization, 13 samples were excluded because of low percentage of tumor cells in the tumor tissues. This report is based on 122 samples, of which 15 duplicates were averaged, resulting in 107 final expression values from 58 tumor and 49 non-tumor tissues from 20 never smokers, 26 former smokers, and 28 current smokers.

Dataset Information

Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

Publications

Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors.

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