Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.

Lihua Liu,Lijuan Lin,Qingyi Wei,Li Su,Edward F Patz,David C Christiani,Hongliang Liu,Sheng Luo,Carolyn Glass

doi:10.3389/fonc.2021.717109

Abstract

Accumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (P trend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.

Highlights

Colorectal and Ovarian Cancer Screening Trial (Lung) cancer remains one of the leading causes of cancer-related mortality in the United States
Among the acquired 18,588 single-nucleotide polymorphisms (SNPs) in195 damage-associated molecular patterns (DAMPs)-related pathway genes, we found 315 SNPs to be significantly associated with the non-small cell lung cancer (NSCLC) overall survival (OS) in the PLCO trial in an additive model (Supplementary Table S3A), of which 9 SNPs remained significant as replicated in the Harvard Lung Cancer Susceptibility (HLCS) dataset with multiple test correction by the Bayesian false discovery probability (BFDP) (Supplementary Table S3B)
We evaluated the associations between 18,588 SNPs of a set of 195 DAMPs-related pathway genes and NSCLC survival by using available genotyping and clinical outcome data from two previously published NSCLC genome-wide association study (GWAS)

Summary

Introduction

Lung cancer remains one of the leading causes of cancer-related mortality in the United States. In 2021, it is estimated that there will be more than 235,000 new cases of and nearly 131,000 will die from lung cancer in the United States [1]. About 85% of lung cancer patients are classified as non-small cell lung cancer (NSCLC), and the majority of these cases present with local progression or distal metastasis at the time of diagnosis [2]. Some cases with an early stage of the disease have a favorable prognosis and could be spared the unnecessary therapy, while for other patients with an advantaged stage, the five-year survival rate remains poor, despite the use of all the available targeted and immune therapies [3].

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Conclusion