Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients

• Published in: International journal of cancer 2019-08, Vol.145 (3), p.621-631
• Main Authors: Chen, Ka, Liu, Hongliang, Liu, Zhensheng, Luo, Sheng, Patz, Edward F., Moorman, Patricia G., Su, Li, Shen, Sipeng, Christiani, David C., Wei, Qingyi
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenosylmethionine Decarboxylase - genetics; Adenosylmethionine Decarboxylase - metabolism; Aged; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Cell survival; Core Binding Factor Alpha 3 Subunit - genetics; Core Binding Factor Alpha 3 Subunit - metabolism; Dependence; Female; Gene expression; Gene mapping; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotypes; Genotyping; Humans; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Male; Medical research; Metabolic pathways; Metabolism; Methionine; Methionine - metabolism; Methionine Sulfoxide Reductases - genetics; Methionine Sulfoxide Reductases - metabolism; Middle Aged; Mutation; Mutation rates; Non-small cell lung carcinoma; nonsmall cell lung cancer; Polymorphism, Single Nucleotide; Proportional Hazards Models; Quantitative Trait Loci; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; ROC Curve; Runx3 protein; Single-nucleotide polymorphism; Survival; Survival Rate
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.32128

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  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 pmeta = 2.86 × 10−6, 0.81 (0.73–0.91) and pmeta = 4.63 × 10−4, and 0.77 (0.68–0.89) and pmeta = 2.07 × 10−4, respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose–response manner (ptrend