Investigation of CD28 Gene Polymorphisms in Patients with Sporadic Breast Cancer in a Chinese Han Population in Northeast China

Abstract

BackgroundCD28 is one of a number of costimulatory molecules that play crucial roles in immune regulation and homeostasis. Accumulating evidence indicates that immune factors influence breast carcinogenesis. To clarify the relationships between polymorphisms in the CD28 gene and breast carcinogenesis, a case-control study was conducted in women from Heilongjiang Province in northeast of China.Methodology/Principal FindingsOur research subjects consisted of 565 female patients with sporadic breast cancer and 605 age- and sex-matched healthy controls. In total, 12 single nucleotide polymorphisms (SNPs) in the CD28 gene were successfully determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relationship between the CD28 variants and clinical features, including histological grade, tumor size, lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR), and tumor protein 53 (P53) status were analyzed. A statistically significant association was observed between rs3116496 and breast cancer risk under different genetic models (additive P = 0.0164, dominant P = 0.0042). Different distributions of the rs3116496 ‘T’ allele were found in patients and controls, which remained significant after correcting the P value for multiple testing using Haploview with 10,000 permutations (corrected P = 0.0384). In addition, significant associations were observed between rs3116487/rs3116494 (D’ = 1, r2 = 0.99) and clinicopathological features such as C-erbB2 and ER status, in breast cancer patients.Conclusions/SignificanceOur findings indicate that CD28 gene polymorphisms contribute to sporadic breast cancer risk and have a significant association with clinicopathological features in a northeast Chinese Han population.

Polymorphisms in CD28, CTLA-4, CD80 and CD86 genes may influence the risk of multiple sclerosis and its age of onset

“…In our study two polymorphisms of CD28 gene were investigated: rs35593994G N A located in the promoter region in putative binding site for transcription factor (as it was shown by in silico analysis) and rs3116496T N C, which according to literature data is located near the splice acceptor site and therefore may contribute to aberrant mRNA splicing (Chen et al, 2012). Similarly to Veen et al (van Veen et al, 2003), we did not observe the association of rs3116496T N C with MS susceptibility.…”

“…Therefore it may contribute to aberrant mRNA splicing. In consequence it could influence immune homeostasis by disturbing balance between different isoforms of CD28 protein (Chen et al, 2012). In fact, the study performed by Ledezma-Lozano et al (Ledezma-Lozano et al, 2011) revealed that in group of rheumatoid arthritis patients, TC genotype in rs3116496T N C was associated with the decreased level of soluble CD28 form in comparison to TT.…”

The association of CD28 polymorphism, rs3116496, with Cancer: A meta-analysis

“…Costimulatory molecules play crucial roles in regulating T and B cell immune responses and homeostasis [15][16][17][18][19]. In particular, members of the cluster of differentiation (CD) family, including CD28, cytotoxic T-lymphocyte antigen 4, and inducible T-cell costimulator, are major costimulatory molecules [15][16][17][18][19][20]. CD28 is constitutively expressed on the majority of naïve T cells, while the others are expressed on activated T cells [21][22][23][24][25].…”

“…CD28 is constitutively expressed on the majority of naïve T cells, while the others are expressed on activated T cells [21][22][23][24][25]. CD28 interacts with B7-1 and B7-2 on antigen-presenting cells (APCs) and induces T cell differentiation and proliferation [15,20,[26][27][28][29][30]. In addition, CD28 has been shown to enhance glucose uptake, glycolysis, production of cytokines such as interleukin-2, and cell survival through induction of the antiapoptotic factor Bcl-XL [31][32][33][34][35][36][37][38][39][40][41][42].…”

“…Many studies have examined the association between CD28 polymorphism and cancer incidence in various populations. Polymorphisms in rs1181388, rs1181390, rs3116487, rs3116494, rs3116496, rs3181097, rs3181098, rs3181110, rs3181101, rs3181107, rs3181113, rs3769684, rs3769686, rs4673259, rs10932017, rs12693993, and rs35593994 affect the incidence of breast cancer [15], non-small cell lung cancer [28], cervical cancer [23,47], malignant melanoma [48], colorectal cancer [49], B cell chronic lymphoblastic leukemia [50], and other cancer types. In particular, polymorphisms in rs3116496 have been widely studied for their connection to cancer, while polymorphisms in other positions are quite limited in numbers.…”