Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
Duke Cancer Institute, Duke University Medical Center, Durham, NC.
Int J Cancer. 2019 Aug 1;145(3):621-631. doi: 10.1002/ijc.32128. Epub 2019 Feb 1.
Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in nonsmall cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (p < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295 G > T, AMD1 rs1279590 G > A and MSRA rs73534533 C > A) were replicated in the validation dataset, and their meta-analysis showed an adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and p = 2.86 × 10 , 0.81 (0.73-0.91) and p = 4.63 × 10 , and 0.77 (0.68-0.89) and p = 2.07 × 10 , respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (p < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (p < 0.0001 and < 0.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients.
癌细胞中异常的蛋氨酸依赖性导致蛋氨酸限制成为一种潜在的治疗策略。我们假设，参与蛋氨酸代谢基因的遗传变异与非小细胞肺癌 (NSCLC) 患者的生存有关。因此，我们使用来自两个已发表的全基因组关联研究 (GWAS) 数据集的基因分型数据，研究了 97 个蛋氨酸代谢途径基因中的 16378 个常见单核苷酸多态性 (SNP) 与 NSCLC 患者总生存期 (OS) 的关联。在单基因座分析中，在发现数据集的 1005 个 SNP 与 NSCLC OS 显著相关 (p < 0.05，假阳性报告概率 < 0.2)。三个 SNP (RUNX3 rs7553295 G > T、AMD1 rs1279590 G > A 和 MSRA rs73534533 C > A) 在验证数据集中得到复制，其荟萃分析显示调整后的危险比 [HR] 为 0.82 [95%置信区间 (CI) =0.75-0.89]，p = 2.86×10-4，0.81 (0.73-0.91) 和 p = 4.63×10-4，0.77 (0.68-0.89) 和 p = 2.07×10-4。这三个 SNP 的保护性基因型的遗传评分显示出一种与剂量相关的增加 OS 的趋势 (p < 0.0001)。进一步的表达数量性状基因座 (eQTL) 分析表明，这些基因型与 mRNA 表达水平之间存在显著关联。此外，差异表达分析进一步支持 MSRA 的肿瘤抑制作用，肺鳞癌和腺癌中的 mRNA 水平均低于相邻正常组织 (p < 0.0001 和 p < 0.0001)。此外，这三个基因的低突变率表明这些功能 SNP 在癌症进展中起着关键作用。综上所述，这些蛋氨酸代谢途径基因的遗传变异可能是 NSCLC 患者生存的有希望的预测因子。
