Genetic variants of BIRC3 and NRG1 in the NLRP3 inflammasome pathway are associated with non-small cell lung cancer survival.
Abstract
The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes,
and its genetic variation and functional dysregulation are involved in pathogenesis
of several cancers. To systematically evaluate the role of NLRP3 in predicting outcomes
of patients with non-small cell lung cancer (NSCLC), we performed a two-phase analysis
for associations between genetic variants in NLRP3 inflammasome pathway genes and
NSCLC survival by using a published genome-wide association study (GWAS) dataset from
the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We used
multivariate Cox proportional hazards regression analysis with Bayesian false discovery
probability (≤0.80) for multiple testing correction to evaluate associations between
20,730 single-nucleotide polymorphisms (SNPs) in 176 genes and overall survival of
1,185 NSCLC patients from the PLCO trial. We further validated the identified significant
SNPs in another GWAS dataset with survival data from 984 NSCLC patients of the Harvard
Lung Cancer Susceptibility (HLCS) study. The results showed that two independent SNPs
in two different genes (i.e., BIRC3 rs11225211 and NRG1 rs4733124) were significantly
associated with the NSCLC overall survival, with a combined hazards ratio (HR) of
0.83 [95% confidence interval (CI) = 0.74-0.93 and P = 0.0009] and 1.18 (95% CI =
1.06-1.31) and P = 0.002], respectively. However, further expression quantitative
trait loci (eQTL) analysis showed no evidence for correlations between the two SNPs
and mRNA expression levels of corresponding genes. These results indicated that genetic
variants in the NLRP3 imflammasome pathway gene-sets might be predictors of NSCLC
survival, but the molecular mechanisms underlying the observed associations warrant
further investigations.
Type
Journal articleSubject
NLRP3 inflammasomeNon-small cell lung cancer
genome-wide association study
overall survival
single-nucleotide polymorphism
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Sheng Luo
Professor of Biostatistics & Bioinformatics
Edward F. Patz Jr.
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 ex
Qingyi Wei
Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director
for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology
and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally
recognized epidemiologist focused on the molecular and genetic epidemiology of head
and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and
genetic determinants for the DNA repair deficient phenotype and
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