Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma-specific survival

Ka Chen, Hongliang Liu, Zhensheng Liu, Wendy Bloomer, Christopher I. Amos, Jeffrey E. Lee, Xin Li, Hongmei Nan, Qingyi Wei

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single-nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM-specific survival (CMSS) using genotyping datasets from two published genome-wide association studies (GWASs). In the single-locus analysis, 76 SNPs were found to be significantly associated with CMSS (P <.050, false-positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect-allele attributed adjusted hazards ratio of 1.52 (95% confidence interval = 1.19-1.93) and P <.001, 0.68 (0.54-0.87) and P =.002 and 0.62 (0.46-0.83) and P =.002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five-year CMSS prediction (P =.012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 −11) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun-exposed skin of the lower leg (P = 6.62 × 10−6 and 1.37 × 10−7, respectively) and in sun-not-exposed suprapubic skin (P <.001 and 1.43 × 10−8, respectively). Taken together, these genetic variants of glutamine-metabolic pathway genes may be promising predictors of survival in patients with CM.

Original languageEnglish (US)
JournalMolecular Carcinogenesis
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Metabolic Networks and Pathways
Glutamine
Melanoma
Skin
Survival
Single Nucleotide Polymorphism
Genes
Alleles
Solar System
Genotype
Messenger RNA
Quantitative Trait Loci
Genome-Wide Association Study
Leg
Genome
Databases
Confidence Intervals
Cell Line
Datasets

Keywords

  • cutaneous melanoma
  • genome-wide association study
  • glutamine
  • single-nucleotide polymorphism
  • survival

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Chen, K., Liu, H., Liu, Z., Bloomer, W., Amos, C. I., Lee, J. E., ... Wei, Q. (Accepted/In press). Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma-specific survival. Molecular Carcinogenesis. https://doi.org/10.1002/mc.23100

Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma-specific survival. / Chen, Ka; Liu, Hongliang; Liu, Zhensheng; Bloomer, Wendy; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Wei, Qingyi.

In: Molecular Carcinogenesis, 01.01.2019.

Research output: Contribution to journalArticle

Chen, Ka ; Liu, Hongliang ; Liu, Zhensheng ; Bloomer, Wendy ; Amos, Christopher I. ; Lee, Jeffrey E. ; Li, Xin ; Nan, Hongmei ; Wei, Qingyi. / Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma-specific survival. In: Molecular Carcinogenesis. 2019.
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abstract = "Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single-nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM-specific survival (CMSS) using genotyping datasets from two published genome-wide association studies (GWASs). In the single-locus analysis, 76 SNPs were found to be significantly associated with CMSS (P <.050, false-positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect-allele attributed adjusted hazards ratio of 1.52 (95{\%} confidence interval = 1.19-1.93) and P <.001, 0.68 (0.54-0.87) and P =.002 and 0.62 (0.46-0.83) and P =.002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five-year CMSS prediction (P =.012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 −11) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun-exposed skin of the lower leg (P = 6.62 × 10−6 and 1.37 × 10−7, respectively) and in sun-not-exposed suprapubic skin (P <.001 and 1.43 × 10−8, respectively). Taken together, these genetic variants of glutamine-metabolic pathway genes may be promising predictors of survival in patients with CM.",
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