The association of BTLA gene polymorphisms with non-small lung cancer risk in smokers and never-smokers

Abstract

IntroductionLung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between BTLA gene variants and susceptibility to chronic lymphoblastic leukemia and renal cell carcinoma in the Polish population. The present study aimed to analyze the impact of BTLA polymorphic variants on the susceptibility to NSCLC and NSCLC patients’ overall survival (OS).MethodsUsing TaqMan probes we genotyped seven BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669 and rs2633582 with the use of ViiA 7 Real-Time PCR System.ResultsWe found that rs1982809 within BTLA is associated with NSCLC risk, where carriers of rs1982809G allele (AG+GG genotypes) were more frequent in patients compared to controls. In subgroup analyses, we also noticed that rs1982809G carriers are significantly overrepresented in never-smokers, but not in smokers compared to controls. Additionally, the global distribution of the haplotypes differed between the never-smokers and smokers, where haplotypes A G G C A, C G A C G, and C G A T G were more frequent in never-smoking patients. Furthermore, the presence rs1982809G (AG+GG genotypes) allele as well as the presence of rs9288953T allele (CT+TT genotypes) increased NSCLC risk in females’ patients. After stratification by histological type, we noticed that rs1982809G and rs2705511C carriers were more frequent among adenocarcinoma patients. Moreover, rs1982809G and rs2705511C correlated with the more advanced stages of NSCLC (stage II and III), but not with stage IV. Furthermore, we showed that rs2705511 and rs1982809 significantly modified OS, while rs9288952 tend to be associated with patients’ survival.ConclusionOur results indicate that BTLA polymorphic variants may be considered low penetrating risk factors for NSCLC especially in never-smokers, and in females, and are associated with OS of NSCLC patients.

The Methylation in B7-H4 and BTLA Genes are Associated with the Risk of Pulmonary Tuberculosis

“…Andrzejczak et al found that rs1982809 variant was significantly related to non-small cell lung cancer risk. 30 Karabon et al reported that rs1982809, rs9288953 variants would affect the susceptibility to chronic lymphocytic leukemia. 31 It was worth noting that rs9288953 variant was found to be significantly associated with the development of drug resistance among PTB patients.…”

BTLA biology in cancer: from bench discoveries to clinical potentials

“…In one of our studies by Andrzejczak et al we investigated the correlation between seven BTLA SNPs: rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669, and rs2633582, and susceptibility to NSCLC in 383 cases and 474 HC in the Polish population. It was found that the rs1982809 SNP was associated with NSCLC risk, where carriers of the rs1982809 G allele were more frequent in NSCLC patients compared to HC [ 122 ]. Our results were consistent with Khadhraoui’s study [ 121 ].…”

“…In addition, haplotype global distribution differed between never-smokers and smokers, where CGACG, CGATG, and AGGCA (rs2705511, rs1982809, rs9288952, rs9288953, rs1844089) haplotypes were more frequent in never-smokers. After stratification by gender, females carrying the rs1982809 G allele or the rs9288953 T allele had a higher risk of NSCLC by 1.6 and 2.2 times, respectively When disease stage was taken in to consideration, rs1982809 G and rs2705511 C alleles were associated with the more advanced stages of NSCLC (stage II and III), but not with stage IV [ 122 ]. Moreover, similarly to Khadhraoui’s study [ 121 ], we noticed a higher risk of adenocarcinoma in patients bearing the rs1982809 AG genotype.…”

“…Moreover, similarly to Khadhraoui’s study [ 121 ], we noticed a higher risk of adenocarcinoma in patients bearing the rs1982809 AG genotype. The Kaplan-Meier analysis revealed that rs1982809 and rs2705511 significantly modified patient OS [ 122 ].…”

“…Of equal importance, subgroup analysis of much more homogenous cohorts can reveal associations not noticed in heterogenous groups. This can be clearly seen for example when NSCLC patients were divided into subgroups based on histological subtype [ 122 , 123 ]. Similarly, smoking status may be the factor masking the influence of low penetrating risk factors like BTLA SNPs, which was found for NSCLC [ 122 ] and EGJA [ 124 ].…”