Influence of CTLA-4/CD28/ICOS gene polymorphisms on the susceptibility to cervical squamous cell carcinoma and stage of differentiation in the Polish population

Abnormal expressions of the costimulatory molecules CD28, "inducible co-stimulator" (ICOS), and inhibitory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) lead to disturbances of immune response and entail an increased risk of cancer. This study was undertaken to evaluate the association between the polymorphisms CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60), CD28c.17+3T>C, and ICOSc.1554+4GT(8_15), and susceptibility to CSCC. The association between CTLA-4g.319C>T[T] allele and [TT+CT] genotype and susceptibility to CSCC was observed (OR = 1.99, p = 0.003, and OR = 2.07, p = 0.005, respectively). The CTLA-4g.319C>T[T] allele and [TT+CT] genotype increased the risk of well-differentiated CSCC by a factor of 3.84 and 4.44 (p = 0.00001, and p = 0.00001, respectively). In patients with moderately differentiated CSCC, a trend toward increased frequency of CTLA-4g.319C>T[T] allele and CTLA-4g.319C>T[TT+CT] genotype was noticed (OR = 1.68, p = 0.09, and OR = 1.75, p = 0.09, respectively), whereas in low differentiated CSCC such relation was not observed. Both CTLA-4g.*642AT(8_33) [(AT)(8)]/[(AT)(8)] homozygote and [(AT)(8)] allele were overrepresented in CSCC patients in comparison with healthy women (p = 0.004, OR = 1.93, and p = 0.03, OR = 1.41, respectively) but this polymorphism was not related to histologic grade of tumor. CD28c.17+3T>C polymorphism was not associated with susceptibility to CSCC in whole group of patients, but CD28c.17+3T>C[C] allele and CD28c.17+3T>C[CC+TC] genotype were more frequently observed among well differentiated CSCC patients compared with controls (OR = 1.89, p = 0.05, and OR = 2.05, p = 0.05, respectively). Other studied polymorphisms were not associated with susceptibility to CSCC and with histologic grade of CSCC. Our results suggest that the CTLA-4 gene is susceptibility gene to CSCC especially to well-differentiated tumor, while association between CD28 gene polymorphism and disease is restricted only to the well-differentiated CSCC.