Dataset Information

Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.

ABSTRACT: The toll-like receptor (TLR) signaling pathway plays an important role in the innate immune responses and antigen-specific acquired immunity. Aberrant activation of the TLR pathway has a significant impact on carcinogenesis or tumor progression. Therefore, we hypothesize that genetic variants in the TLR signaling pathway genes are associated with overall survival (OS) of patients with non-small cell lung cancer (NSCLC). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate associations between genetic variants of 165 TLR signaling pathway genes and NSCLC OS using the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). The results were further validated by the Harvard Lung Cancer Susceptibility GWAS dataset. Specifically, we identified IRAK2 rs779901 C > T as a predictor of NSCLC OS, with a variant-allele (T) attributed hazards ratio (HR) of 0.78 [95% confidence interval (CI) = 0.67-0.91, P = 0.001] in the PLCO dataset, 0.84 (0.72-0.98, 0.031) in the Harvard dataset, and 0.81 (0.73-0.90, 1.08x10-4 ) in the meta-analysis of these two GWAS datasets. In addition, the T allele was significantly associated with an increased mRNA expression level of IRAK2. Our findings suggest that IRAK2 rs779901 C > T may be a promising prognostic biomarker for NSCLC OS.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6205899 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.

Xu Yinghui Y Liu Hongliang H Liu Shun S Wang Yanru Y Xie Jichun J Stinchcombe Thomas E TE Su Li L Zhang Ruyang R Christiani David C DC Li Wei W Wei Qingyi Q

International journal of cancer 20180921 10

The toll-like receptor (TLR) signaling pathway plays an important role in the innate immune responses and antigen-specific acquired immunity. Aberrant activation of the TLR pathway has a significant impact on carcinogenesis or tumor progression. Therefore, we hypothesize that genetic variants in the TLR signaling pathway genes are associated with overall survival (OS) of patients with non-small cell lung cancer (NSCLC). To test this hypothesis, we first performed Cox proportional hazards regress ...[more]

PMID: 29978465

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Project description:Although lymphangiogenesis is a vital step in lung cancer metastasis, the association between lymphangiogenesis and non-small cell lung cancer (NSCLC) survival remains unclear. Since single-nucleotide polymorphisms (SNPs) have been reported to predict NSCLC survival, we investigated associations between SNPs in lymphangiogenesis-related pathway genes and NSCLC survival in a discovery genotyping dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility Study. We evaluated associations between 34,509 genetic variants (3252 genotyped and 31,257 imputed) in 247 genes involved in lymphangiogenesis-related pathway and NSCLC survival. After validation, we finally identified two independent SNPs (SYK rs11787670 A>G and ITGA1 rs67715745 T>C) to be significantly associated with NSCLC overall survival (OS), with adjusted hazards ratios of 0.77 and 0.83 (95% confidence interval =0.66-0.90, P=7.20×10-4) and 0.84 (95% confidence interval =0.75-0.92, P=3.50×10-4), respectively. Moreover, an increasing number of combined protective alleles of these two SNPs was significantly associated with an improved NSCLC OS and disease-specific survival (DSS) in the PLCO dataset (P trend=0.011 and 0.006, respectively). Furthermore, the addition of these protective alleles to the prediction model for the 5-year survival increased the time-dependent area under the curve both from 87% to 87.67% for OS (P=0.029) and from 88.54% to 89.06% for DSS (P=0.022). Subsequent expression quantitative trait loci (eQTL) functional analysis revealed that the rs11787670 G allele was significantly associated with an elevated SYK mRNA expression in normal tissues. Additional analyses suggested a suppressor role for both SYK and ITGA1 in NSCLC survival. Collectively, these findings indicated that SYK rs11787670 A>G and ITGA1 rs67715745 T>C may be independent prognostic factors for NSCLC survival once further validated.

Dataset Information

Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.

Publications

Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer.

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