Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small 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. This article is protected by copyright. All rights reserved.

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10.1002/ijc.32128

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Chen, Ka, Hongliang Liu, Zhensheng Liu, Sheng Luo, Edward F Patz, Patricia G Moorman, Li Su, Sipeng Shen, et al. (2019). Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients. International journal of cancer. 10.1002/ijc.32128 Retrieved from https://hdl.handle.net/10161/17935.

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Patz

Edward F. Patz

James and Alice Chen Distinguished Professor of Radiology

There are numerous ongoing clinical studies primarily focused on the early detection of cancer.

The basic science investigations in our laboratory concentration on three fundamental translational areas,

1) Development of molecular imaging probes - We have used several different approaches to develop novel imaging probes that characterize and phenotype tumors.

2) Discovery of novel lung cancer biomarkers - We explored the use of proteomics, autoantibodies, and genomics to discover blood and tissue biomarkers for early cancer detection and phenotyping of cancer.

3) Host response to cancer - We study the native immune response to tumors as this may provide cues to relevant diagnostic and therapeutic targets. Most recently we have focused on intratumoral lymphocytes and their specific tumor antigens.

 


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