TP53 常见变异与 PPP1R13L 和 CD3EAP 单核苷酸多态性及中国人群肺癌风险和吸烟行为的相互作用。
TP53 common variants and interaction with PPP1R13L and CD3EAP SNPs and lung cancer risk and smoking behavior in a Chinese population.
机构信息
Key Laboratory of Environment and Population Health of Liaoning Education Ministry (Shenyang Medical College), Shenyang, Liaoning Province, People's Republic of China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China.
出版信息
Biomed J. 2022 Feb;45(1):169-178. doi: 10.1016/j.bj.2021.01.006. Epub 2021 Jan 29.
BACKGROUND
TP53 encodes a tumor suppressor protein containing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The effect of TP53 inactivation is well-known, and genetically determined smaller variations in TP53 activity are related to cancer. Lung cancer causes the highest rates of morbidity and mortality in the world. Epidemiology studies have assessed the association of TP53 single nucleotide polymorphisms with lung cancer.
METHODS
We systematically examined the association of five htSNPs (haplotype-tagging single nucleotide polymorphism) (rs12951053, rs1042522, rs8079544, rs12602273 and rs8064946) across the entire TP53 locus and interaction between genes TP53 and PPP1R13L and CD3EAP and smoking-duration related to lung cancer risk in this Chinese study including 544 cases and 550 controls.
RESULTS
No significant associations were observed in analysis of alleles and genotypes with co-dominant, dominant, recessive, and log-additive models after adjustment for smoking status. Haplotype analysis showed that haplotype9 (rs12951053-rs1042522-rs8079544-rs12602273-rs8064946) [OR (95% CI) = 0.13 (0.03-0.59), p = 0.0079] was associated with decreased risk of lung cancer after adjusted for smoking-duration. The analysis of smoking-duration within TP53 haplotypes showed that there were more carriers of haplotype1 (AGCCG), 2 (CCCGC) and 4 (CCCCG) in smoking-subgroup of >20 (years) (all p < 0.05). MDR testing analysis identified two significant models (both p < 0.0010) of gene-gene-environment interaction in relation to lung cancer risk in whole study group.
CONCLUSION
The present results provide novel evidence that the haplotype of TP53 htSNPs and interaction between genetic variation in TP53 and CD3EAP and smoking-duration may associate with lung cancer risk, and provide additional evidence of association between TP53 htSNP haplotypes and long-term smoking-related behavior.
背景
TP53 基因编码一种肿瘤抑制蛋白，具有细胞周期阻滞、凋亡、衰老、DNA 修复或代谢改变等功能。TP53 失活的影响众所周知，而 TP53 活性的遗传决定的较小变化与癌症有关。肺癌是世界上发病率和死亡率最高的癌症。流行病学研究已经评估了 TP53 单核苷酸多态性与肺癌的相关性。
方法
我们系统地研究了整个 TP53 基因座中的五个 htSNPs（单倍型标记单核苷酸多态性）（rs12951053、rs1042522、rs8079544、rs12602273 和 rs8064946）与肺癌风险之间的关联，以及基因 TP53 与 PPP1R13L 和 CD3EAP 之间的相互作用与吸烟时间的关系。本研究包括 544 例病例和 550 例对照。
结果
在调整吸烟状况后，用共显性、显性、隐性和对数相加模型分析等位基因和基因型，均未观察到显著关联。单倍型分析显示，单倍型 9（rs12951053-rs1042522-rs8079544-rs12602273-rs8064946）[比值比（95%置信区间）= 0.13（0.03-0.59），p=0.0079]与调整吸烟时间后肺癌风险降低相关。在 TP53 单倍型内吸烟时间的分析中，在吸烟时间大于 20 年的亚组中，携带单倍型 1（AGCCG）、2（CCCGC）和 4（CCCCG）的人数更多（均 p<0.05）。MDR 检测分析确定了两个与全组肺癌风险相关的基因-基因-环境相互作用的显著模型（均 p<0.0010）。
结论
本研究结果提供了新的证据，表明 TP53 htSNPs 单倍型和 TP53 基因与 CD3EAP 之间遗传变异与吸烟时间的相互作用可能与肺癌风险相关，并提供了 TP53 htSNP 单倍型与长期吸烟相关行为之间关联的额外证据。
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