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Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial.

Publication ,  Journal Article
Guo, Y; Feng, Y; Liu, H; Luo, S; Clarke, JW; Moorman, PG; Su, L; Shen, S; Christiani, DC; Wei, Q
Published in: Mol Carcinog
July 2019

The tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non-small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively. We selected 6788 SNPs in 71 genes in the TNF/TNFR signaling pathway and extracted their genotyping data from the PLCO genowide-association study (GWAS) dataset. We performed Cox proportional hazards regression analysis to evaluate associations between the identified SNPs and survival and validated the significant SNPs, which were further analyzed for their functional relevance. We found that genotypes of two validated SNPs, IKBKAP rs4978754 CT + TT and TNFRSF1B rs677844 TC + CC, as well as their combined genotypes predicted a better overall survival (P = 0.004, 0.002 and <0.001, respectively). These two validated SNPs were predicted by the RegulomeDB score to be potentially functional. In addition, IKBKAP mRNA expression levels were significantly higher, while TNFRSF1B mRNA expression levels were significantly lower in lung cancer tissues than in adjacent normal tissues (P < 0.001). The Cancer Genome Atlas (TCGA)-based expression quantitative trait loci analysis showed that IKBKAP rs4978754 and TNFRSF1B rs677844 genotypes were significantly associated with their corresponding mRNA expression levels in lung cancer tissues in a recessive model (P = 0.035 and 0.045, respectively). Therefore, we identified two potentially functional SNPs (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with NSCLC.

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Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

July 2019

Volume

58

Issue

7

Start / End Page

1094 / 1104

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transcriptional Elongation Factors
  • Signal Transduction
  • Receptors, Tumor Necrosis Factor, Type II
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans
  • Genome-Wide Association Study
 

Citation

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Guo, Y., Feng, Y., Liu, H., Luo, S., Clarke, J. W., Moorman, P. G., … Wei, Q. (2019). Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial. Mol Carcinog, 58(7), 1094–1104. https://doi.org/10.1002/mc.23017
Guo, Yi, Yun Feng, Hongliang Liu, Sheng Luo, Jeffrey W. Clarke, Patricia G. Moorman, Li Su, Sipeng Shen, David C. Christiani, and Qingyi Wei. “Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial.Mol Carcinog 58, no. 7 (July 2019): 1094–1104. https://doi.org/10.1002/mc.23017.
Guo Y, Feng Y, Liu H, Luo S, Clarke JW, Moorman PG, Su L, Shen S, Christiani DC, Wei Q. Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial. Mol Carcinog. 2019 Jul;58(7):1094–1104.
Journal cover image

Published In

Mol Carcinog

DOI

EISSN

1098-2744

Publication Date

July 2019

Volume

58

Issue

7

Start / End Page

1094 / 1104

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transcriptional Elongation Factors
  • Signal Transduction
  • Receptors, Tumor Necrosis Factor, Type II
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans
  • Genome-Wide Association Study