AUTHOR=Lu Guojun , Liu Hongliang , Wang Huilin , Tang Xiaozhun , Luo Sheng , Du Mulong , Christiani David C. , Wei Qingyi 

TITLE=Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1440454

DOI=10.3389/fimmu.2024.1440454

ISSN=1664-3224

ABSTRACT=<p>B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (<italic>P</italic> ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (<italic>INPP5D</italic>) rs13385922 C&gt;T and exosome component 3 (<italic>EXOSC3</italic>) rs3208406 A&gt;G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, <italic>P</italic> = 2.41×10<sup>-4</sup>) and 1.20 (95% confidence interval = 1.14-1.28, <italic>P</italic> = 3.41×10<sup>-9</sup>), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (<italic>P</italic><sub>trend</sub> = 0.0002) and disease-specific survival (DSS, <italic>P</italic><sub>trend</sub> &lt; 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the <italic>INPP5D</italic> rs6782875 T allele was significantly correlated with elevated <italic>INPP5D</italic> mRNA expression levels in normal lung tissues and whole blood samples, while the <italic>EXOSC3</italic> rs3208406 G allele was significantly correlated with increased <italic>EXOSC3</italic> mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.</p>