Polymorphisms in immune checkpoint genes might influence bladder cancer risk and clinical outcome

In addition to well-established immune checkpoints (ICs), such as CTLA-4, PD-1, PD-L1, increasing attention is being directed toward next-generation ICs, including TIM-3, Gal-9, LAG-3, BTLA, HVEM, and CD160. Single nucleotide polymorphisms (SNPs) within IC-related genes may contribute to dysregulation of inhibitory pathways and impair anti-tumor immune responses. This study aimed to evaluate the association between selected IC gene variants and susceptibility to bladder cancer (BC).

A total of twelve SNPs located in TIM-3, LGALS9, BTLA, HVEM, and CD160 genes were genotyped using TaqMan assays in 314 BC patients and over 520 healthy controls (HC). Genotype distributions were analyzed under multiple genetic models, and associations with clinicopathological parameters were assessed using multivariate logistic regression.

Genotype distributions of BTLA polymorphisms (rs2705511, rs1982809, rs9288953) differed between BC patients and HC, suggesting potential associations with BC risk. Stratified analyses revealed sex-specific effects, with variants in BTLA (rs1982809), HVEM (rs1886730, rs2234167, rs8725), and CD160 (rs231375) showing potential associations with susceptibility among women. Additionally, SNPs in BTLA and HVEM were nominally associated with recurrence and high-grade tumors, while CD160 and LGALS9 variants were potentially linked to primary tumor occurrence. However, these associations lost statistical significance after correction for multiple comparisons.

Although the observed associations did not remain significant after multiple testing correction, the results suggest that genetic variation within BTLA, HVEM, and CD160 genes may still play a biologically relevant role in BC susceptibility and disease progression. These findings underscore the potential importance of IC pathways in BC pathogenesis and warrant further investigation in larger, well-powered studies.