Key Laboratory of Environment and Population Health of Liaoning Education Ministry (Shenyang Medical College), Shenyang 110034, 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 100142, People's Republic of China.
Key Laboratory of Environment and Population Health of Liaoning Education Ministry (Shenyang Medical College), Shenyang 110034, Liaoning Province, People's Republic of China.
Chem Biol Interact. 2017 Nov 1;277:74-78. doi: 10.1016/j.cbi.2017.08.018. Epub 2017 Sep 1.
Lung cancer is the most common cause of cancer-related mortality worldwide. The GADD45 gene family plays important roles in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, DNA repair and anti-tumor immunity. The 19p13.3-GADD45B encoded protein product is involved in apoptosis and inhibiting tumor growth. To evaluate the association of 19p13.3-GADD45B common variants and lung cancer risk, the present study containing 544 Chinese lung cancer cases and 550 cancer-free controls was conducted. Three htSNPs (haplotype-tagging single nucleotide polymorphism) (rs7354, rs14384, and rs3783501) covering 95% of the common haplotype diversity in 19p13.3-GADD45B and interaction of 19p13.3-GADD45B and 19q13.3-PPP1R13L and 19q13.3-CD3EAP variants and smoking-duration were explored. Genotype and allele frequencies and haplotype distributions of the 19p13.3-GADD45B 3 htSNPs were not associated with lung cancer risk after adjustment for smoking status. 19p13.3-GADD45B rs7354 was associated with lung cancer risk among ≤20 (years) smokers [C/A-A/A versus CC, OR (95% CI) = 3.20 (1.11-9.20), P = 0.025] in a dominant model stratified by smoking duration. MDR (multifactor dimensionality reduction) analyses showed that smoking history as main effect and three-way models (smoking duration, 19p13.3-GADD45B rs3783501, 19q13.3-CD3EAP rs967591) (P = 0.001-0.002) indicated statistically significant association with lung cancer risk. The study identified evidence implicating DNA damage response genes on chromosome 19 in etiology of smoke-exposed lung cancer. In conclusion, our findings demonstrate that 19p13.3-GADD45B rs7354 variant and interaction between 19p13.3-GADD45B rs3783501 and 19q13.3-CD3EAP rs967591 may play a role in association with smoke-exposed lung cancer among Chinese. 19p13.3-GADD45B variants should be further evaluated in large prospective studies with molecular pathological annotations of lung cancer.
肺癌是全球癌症相关死亡的最常见原因。GADD45 基因家族在多种细胞损伤反应中发挥重要作用，包括细胞周期检查点、细胞凋亡、DNA 修复和抗肿瘤免疫。19p13.3-GADD45B 编码的蛋白产物参与细胞凋亡和抑制肿瘤生长。为了评估 19p13.3-GADD45B 常见变异与肺癌风险的关联，本研究纳入了 544 例中国肺癌病例和 550 例无癌症对照。三个 htSNPs（单核苷酸多态性）（rs7354、rs14384 和 rs3783501）覆盖了 19p13.3-GADD45B 常见单倍型多样性的 95%，并探讨了 19p13.3-GADD45B 与 19q13.3-PPP1R13L 和 19q13.3-CD3EAP 变异以及吸烟持续时间的相互作用。在调整吸烟状况后，19p13.3-GADD45B 3 个 htSNPs 的基因型和等位基因频率以及单倍型分布与肺癌风险无关。19p13.3-GADD45B rs7354 与吸烟时间≤20（年）的吸烟者肺癌风险相关[C/A-A/A 与 CC，OR（95%CI）=3.20（1.11-9.20），P=0.025]，按吸烟持续时间分层的显性模型。MDR（多因子维度缩减）分析表明，吸烟史作为主要效应和三因素模型（吸烟持续时间、19p13.3-GADD45B rs3783501、19q13.3-CD3EAP rs967591）（P=0.001-0.002）与肺癌风险有统计学显著关联。该研究为染色体 19 上的 DNA 损伤反应基因在暴露于烟雾的肺癌发病机制中的作用提供了证据。总之，我们的研究结果表明，19p13.3-GADD45B rs7354 变异以及 19p13.3-GADD45B rs3783501 与 19q13.3-CD3EAP rs967591 之间的相互作用可能与中国人群中暴露于烟雾的肺癌有关。19p13.3-GADD45B 变体应在具有肺癌分子病理注释的大型前瞻性研究中进一步评估。
