| Autor: |
Ferreira AMC; Laboratory of Cancer Genetics, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil., Carron J; Laboratory of Cancer Genetics, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil.; Department of Anesthesiology, Oncology and Radiology, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil., Gomez GVB; Laboratory of Cancer Genetics, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil., Vazquez VL; Melanoma and Sarcoma Surgery Department, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil., Serrano SV; Department of Medical Oncology, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil., Lourenço GJ; Laboratory of Cancer Genetics, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil., Lima CSP; Laboratory of Cancer Genetics, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil.; Department of Anesthesiology, Oncology and Radiology, School of Medical Sciences, State University of Campinas, Campinas 13083-970, SP, Brazil. |
| Abstrakt: |
This study aimed to verify whether germline single nucleotide variants (SNV) in CTLA-4 gene, c.-1765C>T, c.-1661A>G, c.-1577G>A, and c.-1478G>A, influence the risk, clinicopathological aspects, and survival of patients with CM, as well as its functional consequences. A total of 432 patients with CM and 504 controls were evaluated. CTLA-4 genotypes were identified by real-time polymerase chain reaction (RT-PCR) and expression of CTLA-4 by quantitative PCR (qPCR) and luciferase assay. Cell cycle, proliferation, apoptosis/necrosis, and migration analyses were performed in SK-MEL-28 and A-375 cell lines modified to present homozygous ancestral or variant genotypes by CRISPR technique. Individuals with the CTLA-4 c.-1577 AA genotype and the combined CTLA-4 c.-1577 and c.-1478 AA + AA genotypes were at 1.60- and 3.12-fold higher risk of developing CM, respectively. The CTLA-4 c.-1577 AA genotype was seen as an independent predictor of worse event-free survival and was also associated with higher gene expression, higher cell proliferation, lower cell apoptosis, and higher cell migration. Our data present, for the first time, evidence that CTLA-4 c.-1577G>A alters the risk and clinical aspects of CM treated with conventional procedures and may be used for selecting individuals for tumor prevention and patients for distinct treatment. |
