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

Abstract

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 non-small 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 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta=2.86 x 10−6, 0.81 (0.73-0.91) and Pmeta=4.63 x 10−4, and 0.77 (0.68-0.89) and Pmeta=2.07 x 10−4, respectively). A genetics score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (Ptrend <.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and gene 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 <.0001 and <.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.

Potential Functional Variants in DNA Repair Genes Are Associated with Efficacy and Toxicity of Radiotherapy in Patients with Non-Small-Cell Lung Cancer

“…Fourthly, gene-gene and gene-environment interactions were not analyzed. Additionally, some other important genes, such as ATM gene of DNA-damage sensing [27], ATG16L2 gene related to autophagy [28], and RUNX3 [29] gene in the methionine metabolic pathway that have been reported to be associated with the outcomes of NSCLS, were not included in this study.…”

<p>Influence of Programmed Death Ligand-1-Gene Polymorphism rs822336 on the Prognosis and Safety of Postoperative Patients with NSCLC Who Received Platinum-Based Adjuvant Chemotherapy</p>

“…12 In addition to pathological staging, which serves as the most important prognostic indicator, several factors are of clinical significance for the evaluation of efficacy of platinum-based adjuvant chemotherapy and prognosis, including gene polymorphisms. 13 Furthermore, the licensing of nivolumab and pembrolizumab in mainland Chinabrought new options for patients with advanced NSCLC. 14 PDL1 is one of the most important biomarkers for PD1/PDL1 inhibitors, and indications are that the higher the expression level of PDL1, the better the efficacy of PD1/PDL1 inhibitors.…”

Changes in the Urine Proteome in Patients With Advanced Lung Cancer After Different Drug Treatments

“…It has been reported that methionine biosynthetic process is related to cancer, as many kinds of cancer cells require exogenous methionine to survive 24 . The abnormal dependence of cancer cells on methionine leads to methionine limitation as a potential treatment strategy 25 . Serine, as an important one-carbon donor of the folic acid cycle, can play an antioxidant role because many kinds of cancer cells are highly dependent on it 26 .…”