CTLA-4, CD28, and ICOS Gene Polymorphism Associations with Non-small-cell Lung Cancer

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.