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

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.664474

DOI=10.3389/fimmu.2021.664474

ISSN=1664-3224

ABSTRACT=<p>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 <italic>ERAP1</italic> 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 (<italic>rs26653, rs2287987, rs30187</italic>, and <italic>rs27044</italic>) but one (<italic>rs26618</italic>) in <italic>ERAP1</italic>. No significant associations were seen in other genes. Haplotype analysis indicated that the distribution of many <italic>ERAP1/2</italic> 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 (<italic>ERAP1 rs26653</italic>), disease stage (<italic>ERAP1 rs27044</italic>, <italic>PSMB9 rs17587</italic>), overall survival (<italic>ERAP1 rs30187</italic>), and response to chemotherapy (<italic>ERAP1 rs27044</italic>). The results presented here may suggest the important role for ERAP1 in the anti-cancer response, which is different in smokers <italic>versus</italic> never-smokers, depending to some extent on the presence of ERAP2, and affecting NSCLC clinical course.</p>