Genetic variants in the human leukocyte antigen region and survival of Chinese patients with non-small cell lung carcinoma
Genetic variants in the human leukocyte antigen region and survival of Chinese patients with non-small cell lung carcinoma
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人类白细胞抗原区域的遗传变异与中国非小细胞肺癌患者的生存
DOI：
10.1093/carcin/bgaa066
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发表时间：
2020-09-01
期刊：
影响因子：
4.7
通讯作者：
Zhang, Ruoxin
中科院分区：
文献类型：
--
作者：
Cheng, Lei;Liu, Qi;Zhang, Ruoxin
人类白细胞抗原 (HLA) 具有高度多态性，可驱动抗原呈递、补体级联反应和白细胞针对癌细胞的成熟。因此，我们从一项正在进行的中国非小细胞肺癌（NSCLC）全基因组关联研究中提取了 HLA 区域的基因分型数据。我们使用 10 689 名健康汉族人的深度测序数据，估算 HLA 区域的未分型遗传变异，然后对 1531 名 NSCLC 患者进行两阶段生存分析。在 758 名患者的发现阶段，我们从 15 138 个单核苷酸多态性中鉴定出 301 个与总生存率独立相关 [P < 0.05，贝叶斯错误发现概率 < 0.8J。在另外 773 名患者的进一步验证中，我们确认染色体 6p21、rs241424（位于 TAP2 的内含子 3）和 rs6457642 是两个独立的生存预测因子。在对 1531 名 NSCLC 患者进行的综合分析中，rs241424 G>A 和 rs6457642 C>T 的风险比分别为 1.26 [95% 置信区间 (CI) = 1.14-1.40 和 P = 4.04 x 10(-6)] 和 0.76（95% CI = 0.66-0.87 和 P =分别为 1.16 x 10(-4))。对公开的 ChIP 测序和 Hi-C 数据的分析发现，rs241424 基因座通过与 HLA-DQA1 启动子的长程相互作用参与潜在的顺式调控元件。其他表达数量性状位点分析表明 rs241424 G>A 变化降低了 HLA-DQA1 mRNA 表达。此外，HLA-DQA1在肺癌组织中的表达水平低于癌旁正常组织，且较低的表达水平与肺腺癌患者的预后较差相关。总的来说，HLA 遗传变异可能通过调节 HLA-DQA1 表达的远程启动子相互作用机制来调节 NSCLC 患者的 OS。
Human leukocyte antigen (HLA) is highly polymorphic, driving antigen presentation, complement cascade and leukocyte maturation against cancer cells. Therefore, we extracted genotyping data in the HLA region from an ongoing Chinese genome-wide association study of non-small cell lung cancer (NSCLC). Using deep sequencing data of 10 689 healthy Han Chinese, we imputed for untyped genetic variants in the HLA region, followed by a two-stage survival analysis of 1531 NSCLC patients. In the discovery stage of 758 patients, we identified 301 out of 15 138 single-nucleotide polymorphisms to be independently associated with overall survival [P < 0.05 and Bayesian false-discovery probability < 0.8J. In further validation of another 773 patients, we confirmed chromosome 6p21, rs241424 (located at intron 3 of TAP2) and rs6457642 as two independent survival predictors. In the combined analysis of 1531 NSCLC patients, rs241424 G>A and rs6457642 C>T were associated with a hazards ratio of 1.26 [95% confidence interval (CI) = 1.14-1.40 and P = 4.04 x 10(-6)] and 0.76 (95% CI = 0.66-0.87 and P = 1.16 x 10(-4)), respectively. The analysis of publically available ChIP-sequencing and Hi-C data found that the rs241424 locus was involved in potential cis-regulatory element by a long-range interaction with the HLA-DQA1 promoter. Additional expression quantitative trait loci analysis showed that the rs241424 G>A change decreased HLA-DQA1 mRNA expression. Furthermore, expression levels of HLA-DQA1 were lower in lung cancer tissues than in adjacent normal tissues, and the lower expression was associated with a worse prognosis for patients with lung adenocarcinoma. Collectively, HLA genetic variants may modulate OS of NSCLC patients, possibly via a mechanism of long-range promoter interaction regulating HLA-DQA1 expression.