Dataset Information

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

ABSTRACT: A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ? 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

SUBMITTER: Hosgood HD

PROVIDER: S-EPMC3875137 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

Hosgood H Dean HD Wang Wen-Chang WC Hong Yun-Chul YC Wang Jiu-Cun JC Chen Kexin K Chang I-Shou IS Chen Chien-Jen CJ Lu Daru D Yin Zhihua Z Wu Chen C Zheng Wei W Qian Biyun B Park Jae Yong JY Kim Yeul Hong YH Chatterjee Nilanjan N Chen Ying Y Chang Gee-Chen GC Hsiao Chin-Fu CF Yeager Meredith M Tsai Ying-Huang YH Wei Hu H Kim Young Tae YT Wu Wei W Zhao Zhenhong Z Chow Wong-Ho WH Zhu Xiaoling X Lo Yen-Li YL Sung Sook Whan SW Chen Kuan-Yu KY Yuenger Jeff J Kim Joo Hyun JH Huang Liming L Chen Ying-Hsiang YH Gao Yu-Tang YT Kim Jin Hee JH Huang Ming-Shyan MS Jung Tae Hoon TH Caporaso Neil N Zhao Xueying X Huan Zhang Z Yu Dianke D Kim Chang Ho CH Su Wu-Chou WC Shu Xiao-Ou XO Kim In-San IS Bassig Bryan B Chen Yuh-Min YM Cha Sung Ick SI Tan Wen W Chen Hongyan H Yang Tsung-Ying TY Sung Jae Sook JS Wang Chih-Liang CL Li Xuelian X Park Kyong Hwa KH Yu Chong-Jen CJ Ryu Jeong-Seon JS Xiang Yongbing Y Hutchinson Amy A Kim Jun Suk JS Cai Qiuyin Q Landi Maria Teresa MT Lee Kyoung-Mu KM Hung Jen-Yu JY Park Ju-Yeon JY Tucker Margaret M Lin Chien-Chung CC Ren Yangwu Y Perng Reury-Perng RP Chen Chih-Yi CY Jin Li L Chen Kun-Chieh KC Li Yao-Jen YJ Chiu Yu-Fang YF Tsai Fang-Yu FY Yang Pan-Chyr PC Fraumeni Joseph F JF Seow Adeline A Lin Dongxin D Zhou Baosen B Chanock Stephen S Hsiung Chao Agnes CA Rothman Nathaniel N Lan Qing Q

Human genetics 20120225 7

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in ...[more]

PMID: 22367405

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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 variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

Publications

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

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