Polymorphisms of Antigen-Presenting Machinery Genes in Non-Small Cell Lung Cancer: Different Impact on Disease Risk and Clinical Parameters in Smokers and Never-Smokers.

Andrzej Wiśniewski,Joanna Dubis,Irena Porębska,Wanda Niepiekło-Miniewska,Natalia Jędruchniewicz,Maciej Sobczyński,Aneta Kowal,Piotr Kuśnierczyk,Marta Wagner,Konrad Pawełczyk,Monika Jasek

doi:10.3389/fimmu.2021.664474

Abstract

Lung cancer is strongly associated with cigarette smoking; nevertheless some never-smokers develop cancer. Immune eradication of cancer cells is dependent on polymorphisms of HLA class I molecules and antigen-processing machinery (APM) components. We have already published highly significant associations of single nucleotide polymorphisms (SNPs) of the ERAP1 gene with non-small cell lung cancer (NSCLC) in Chinese, but not in Polish populations. However, the smoking status of participants was not known in the previous study. Here, we compared the distribution of APM polymorphic variants in larger cohorts of Polish patients with NSCLC and controls, stratified according to their smoking status. We found significant but opposite associations in never-smokers and in smokers of all tested SNPs (rs26653, rs2287987, rs30187, and rs27044) but one (rs26618) in ERAP1. No significant associations were seen in other genes. Haplotype analysis indicated that the distribution of many ERAP1/2 haplotypes is opposite, depending on smoking status. Additionally, haplotypic combination of low activity ERAP1 and the lack of an active form of ERAP2 seems to favor the disease in never-smokers. We also revealed interesting associations of some APM polymorphisms with: age at diagnosis (ERAP1 rs26653), disease stage (ERAP1 rs27044, PSMB9 rs17587), overall survival (ERAP1 rs30187), and response to chemotherapy (ERAP1 rs27044). The results presented here may suggest the important role for ERAP1 in the anti-cancer response, which is different in smokers versus never-smokers, depending to some extent on the presence of ERAP2, and affecting NSCLC clinical course.

Highlights

Lung cancer is the most common cause of cancer death
We revealed interesting associations of some antigen-processing machinery (APM) polymorphisms with: age at diagnosis (ERAP1 rs26653), disease stage (ERAP1 rs27044, PSMB9 rs17587), overall survival (ERAP1 rs30187), and response to chemotherapy (ERAP1 rs27044)
Age at Diagnosis and ERAP1 Polymorphism Our analysis revealed that ERAP1 polymorphism influenced age at diagnosis (AAD) of Non-small cell lung cancer (NSCLC) depending on smoking status

Summary

Introduction

Among risk factors of lung cancer, smoking is considered to be the predominant risk factor [1, 2]. Only about 15% of smokers get lung cancer [2]. This disease appears albeit much less frequently (10–25% of all lung cancer cases) among neversmokers [4,5,6]. Non-small cell lung cancer (NSCLC) type accounts for approximately 85% of all cases of lung cancer, especially in never-smokers (almost all cases), and adenocarcinoma is a major type of NSCLC [7,8,9]. Accurate data on the incidence of lung cancer in never-smokers are rare due to the lack of information about smoking habits in the majority of cancer registries [10]

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Discussion

Conclusion