Variation in the gene encoding the co-inhibitory molecule BTLA is associated with survival in patients treated for clear cell renal carcinoma – results of a prospective cohort study

INTRODUCTION: The successful introduction of immune checkpoint blockade approaches to renal-cell carcinoma (RCC) treatment indicates the importance of molecules regulating the T cell response to RCC risk and progression. MATERIAL AND METHODS: In this study, we evaluate the association of variations in the CTLA-4, BTLA and CD28 genes with overall survival (OS) of RCC patients and specifically clear cell RCC (ccRCC) patients. The following single nucleotide polymorphisms (SNPs) previously genotyped using the RFLP method or TaqMan SNP Genotyping Assays were analyzed: CTLA-4 gene: c.49A>G (rs231775), g.319C>T (rs5742909), g.*6230G>A (CT60; rs3087243), g.*10223G>T (Jo31; rs11571302); CD28 gene: c.17+3T>C (rs3116496), c.-1042G>A (rs3181098); BTLA gene: rs2705511, rs1982809, rs9288952, rs9288953, rs2705535 and rs1844089. RESULTS: During long term observation (6.5 years) we discovered that possessing the A allele at BTLA rs1844089 SNP, together with advanced disease (stage ≥ 3, tumor grade > 3, tumor diameter ≥ 70 mm), is an independent risk factor of death which increases the hazard ratio (HR) of death by more than two-fold (HR = 2.21, 95% CI: 1.28–3.83). Furthermore, the OS of patients bearing this allele is 6 months shorter than for homozygous (GG) patients (42.5 vs. 48.2 months). CONCLUSIONS: Our results indicate for the first time that genetic variation within the gene encoding BTLA is significantly associated with overall survival in clear cell renal cell carcinoma patients.