肺鳞状细胞癌的遗传易感性:关于 9q33.2 变异和吸烟的新见解。

IF 3.3 3区 医学 Q2 ONCOLOGY
Huimin Ma, Guoqing Wang, Sunan Miao, Chen Jin, Jiaying Cai, Wenjing Ge, Chang Zhang, Erbao Zhang, Hongxia Ma, Meng Zhu
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引用次数: 0

摘要

全基因组关联研究(GWAS)已经确定了60多个肺癌易感位点,但这些关联的生物学机制在很大程度上仍然未知,尤其是肺鳞状细胞癌(LUSC)。在此,我们整合了3890例LUSC病例和13328例中国后裔的数据,并进行了条件分析,以探索独立的遗传变异,并分析了遗传变异与吸烟的相互作用。我们的研究首次确定了9q33.2区域的遗传变异与吸烟者LUSC风险增加之间的特定关联。在9q33.2中调整标签SNP rs4573350后,未发现其他显著遗传变异。然而,rs4573350与吸烟之间存在显著的叠加性(RERI=1.66, 95%CI: 1.17-2.22, AP=0.26, 95%CI: 0.19-0.33)和多重交互作用(OR=1.30, 95%CI: 1.98 -1.56, P=5.40×10-3)。与CC基因型的非吸烟者相比,CT/TT基因型吸烟者的风险增加了6.29倍(95%CI: 5.46-7.23, P=2.00×10-16)。功能注释发现rs4573350是连锁不平衡区中最强的功能变体。生物学实验证实,rs4573350的T等位基因与香烟烟雾提取物联合暴露可通过调节转录因子FOXA1的结合能力促进ZBTB26的表达。此外,ZBTB26在体外和体内均通过影响PCNA的表达调节LUSC的肿瘤发生,而PCNA参与细胞周期,促进LUSC的肿瘤发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic Susceptibility to Lung Squamous Cell Carcinoma: New Insights on 9q33.2 Variants and Tobacco Smoking.

Genome-wide association studies (GWAS) have identified over 60 susceptibility loci for lung cancer, yet the biological mechanisms underlying these associations remain largely unknown, particularly for lung squamous cell carcinoma (LUSC). Here, we integrated data from 3890 LUSC cases and 13328 controls of Chinese descent, and performed a conditional analysis to explore independent genetic variants and analyzed the interaction between the genetic variants and smoking. Our study was the first to identify a specific association between genetic variants in the 9q33.2 region and increased risk of LUSC in smokers. After adjusting for the tag SNP rs4573350 in 9q33.2, no additional significant genetic variants were found. However, significant additive (RERI=1.66, 95%CI: 1.17-2.22, AP=0.26, 95%CI: 0.19-0.33) and multiple interactions (OR=1.30, 95%CI: 1.08-1.56, P=5.40×10-3) were observed between rs4573350 and smoking. Compared to nonsmokers with the CC genotype, smokers with the CT/TT genotype showed an increased risk of 6.29-fold (95%CI: 5.46-7.23, P=2.00×10-16). Functional annotation identified rs4573350 as the strongest functional variant within the linkage disequilibrium block. Biological experiments confirmed that the combined exposure to the T allele of rs4573350 and cigarette smoke extract promotes the expression of the ZBTB26 by modulating the binding ability of the transcription factor FOXA1. Furthermore, ZBTB26 was found to regulate tumorigenesis of LUSC both in vitro and in vivo by affecting the expression of PCNA, which is involved in cell cycle and promotes tumorigenesis of LUSC.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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