CTLA‐4 and CD28 genes' polymorphisms and renal cell carcinoma susceptibility in the Polish population – a prospective study

Abstract

Polymorphisms in co-stimulatory genes are associated with susceptibility to several malignances such as breast cancer, cervical cancer and chronic lymphocytic leukemia, but have been scarcely investigated in renal cell cancer (RCC). A total of 310 RCC patients and 518 controls were genotyped for single-nucleotide polymorphisms (SNPs) in the CTLA-4 and CD28 genes: CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*6230G>A (CT60; rs3087243), CTLA-4g.*10223G>T (Jo31; rs11571302), CD28c.17+3T>C (rs3116496) and CD28c.-1042G>A (rs3181098). The distribution of the alleles, genotypes and haplotypes in the CTLA-4 and CD28 genes were similar in the RCC patients and in the controls. However, among the patients with a clear cell RCC (CCRCC), the G allele carriers of CT60 and Jo31 SNPs were overrepresented, and the overrepresentation became significant for the carriers of CT60[G] allele in CCRCC patients with necrosis in the primary tumor (P = 0.046). The CTLA-4c.49A>G[A]/CTLA-4g.319C>T[C]/CT60[A]/Jo31[T]/CD28c.17+3T>C[T]/ CD28c.1042G>A[G] haplotype was associated with an approximately threefold increased risk of primary tumor necrosis in CCRCC patients (P corrected = 0.0000007) and with the advanced stage of disease (IV) (P corrected = 0.001). When stratified by gender, CD28c.-1042G>A[GG] genotype was more frequent in the female CCRCC patients compared with healthy women (P = 0.042). Polymorphisms in the CTLA-4 and CD28 genes, in particular considered together as haplotypes, were associated with increased risk of CCRCC, especially with necrosis and with the advanced stage of disease. The CD28c.-1042G>A SNP modulates the risk of CCRCC in women. These findings indicate that the associations of the CTLA-4 and CD28 polymorphisms with the risk of renal cancer are worth further study in a larger group of patients.

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

“…Moreover, there were 30 studies with 9675 cases and 9623 controls for rs3087243 [12-15, 17, 23-25, 27-29, 31, 32, 35, 37, 40, 41, 44, 45, 47, 53, 54, 61, 63, 65, 66, 73-75]. Additionally, rs4553808 was in 17 studies [12, 14, 15, 23, 28, 29, 31, 37, 41, 44, 47, 49, 51, 52, 62, 73, 76], rs5742909 was in 32 studies [12, 14, 15, 20, 24, 25, 28-30, 32, 34, 35, 39-41, 45, 47, 52-54, 56, 57, 59, 62, 63, 65, 66, 70, 73, 76, 77], rs733618 was in 14 studies [13, 23, 28, 37, 44, 47, 51, 52, 62, 73-76, 78], and they were analysed. Of the 67 studies, 9 presented a significant deviation from HWE (5 studies on rs231775 [11, 13, 34, 51, 66], 4 studies on rs4553808 [51, 62…”

Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy

“…Recent studies have suggested thatSNPs [+49 (rs231775), CT60 (rs3087243), −1661 (rs4553808), and −318 (rs5742909)] in the promoter region of CTLA-4 gene may modulate the gene expression and are associated with susceptibility to different types of malignances, such as colorectal cancer [45,46], breast cancer [43], hepatocellular carcinoma [47,48], cervical cancer [48][49][50], melanoma [51], head and neck cancer [52], NSCLC [53,54], renal cell carcinoma [55]and others [56] (Fig. 1B).…”

Is the Genetic Background of Co-Stimulatory CD28/CTLA-4 Pathway the Risk Factor for Prostate Cancer?

“…Interestingly, the association of the both SNPs with another urinary cancer -clear cell renal cell cancer was found by our group [55]. An increasing number of studies have been devoted to the association between the CT60 and Jo31 SNPs and cancers.…”