Du Hailei, Mu Rui, Liu Lihua, Liu Hongliang, Luo Sheng, Patz Edward F, Glass Carolyn, Su Li, Du Mulong, Christiani David C, Li Hecheng, Wei Qingyi
Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
Transl Lung Cancer Res. 2022 May;11(5):890-901. doi: 10.21037/tlcr-22-104.
Lymphocyte activation is part of a complex microenvironment that affects the development and progression of solid tumors. The present study analyzed the associations between genetic variants in lymphocyte activation-related genes and survival of patients with non-small cell lung cancer (NSCLC).
Our study evaluated the associations of 14,400 (1,599 genotyped and 12,801 imputed) single-nucleotide polymorphisms (SNPs) in 176 lymphocyte activation pathway-related genes with survival of 1,185 NSCLC patients in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 984 NSCLC patients from the Harvard Lung Cancer Susceptibility (HLCS) trial.
Multivariable Cox proportional hazards regression analyses identified two distinct and possibly functional variants in forkhead box P1 (; rs2568847 G>C) and RAR-related orphan receptor A (; rs922782 T>G) that were significantly and independently associated with overall survival (OS) [adjusted hazards ratios (HRs) of 1.21 and 0.82, respectively; 95% confidence intervals (CI), 1.11 to 1.32 and 0.76 to 0.88, respectively; P=5.38×10 and 2.68×10, respectively]. Combined analysis of the unfavorable genotypes showed a significant correlation with both OS and disease-specific survival (DSS) in patients with NSCLC patients from PLCO trial (both P<0.0001). Further expression quantitative trait loci (eQTL) analysis using mRNA expression and genotype data in the 1000 Genomes Project demonstrated that the rs922782 G allele predicted mRNA expression levels.
Genetic variants in and of the lymphocyte activation pathway may be promising predictors of NSCLC survival. The rs922782 G allele may predict NSCLC survival, possibly by controlling mRNA expression.
淋巴细胞活化是影响实体瘤发生和发展的复杂微环境的一部分。本研究分析了淋巴细胞活化相关基因的遗传变异与非小细胞肺癌（NSCLC）患者生存之间的关联。
我们的研究评估了176个淋巴细胞活化途径相关基因中的14400个（1599个基因分型和12801个推算）单核苷酸多态性（SNP）与前列腺、肺、结肠和卵巢（PLCO）癌症筛查试验中1185例NSCLC患者生存的关联，并在来自哈佛肺癌易感性（HLCS）试验的另一个984例NSCLC患者的独立数据集中验证了结果。
多变量Cox比例风险回归分析确定了叉头框P1（rs2568847 G>C）和维甲酸相关孤儿受体A（rs922782 T>G）中的两个不同且可能具有功能的变异，它们与总生存期（OS）显著且独立相关[调整后的风险比（HR）分别为1.21和0.82；95%置信区间（CI）分别为1.11至1.32和0.76至0.88；P值分别为5.38×10和2.68×10]。对不良基因型的联合分析显示，在PLCO试验的NSCLC患者中，与OS和疾病特异性生存期（DSS）均显著相关（P均<0.0001）。使用千人基因组计划中的mRNA表达和基因型数据进行的进一步表达定量性状位点（eQTL）分析表明，rs922782 G等位基因可预测mRNA表达水平。
淋巴细胞活化途径中FOXP1和RORA的遗传变异可能是NSCLC生存的有前景的预测指标。rs922782 G等位基因可能通过控制RORA mRNA表达来预测NSCLC生存。
