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Influence of polymorphisms in JAK/STAT pathway genes on the susceptibility and clinicopathological aspects of patients with cutaneous melanoma

Grant number: 16/25407-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2017
Effective date (End): November 30, 2020
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Carmen Silvia Passos Lima
Grantee:Gabriela Vilas Bôas Gomez
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):19/16776-4 - Functional consequences of the STAT3 c.-1937C>G genetic variant on cutaneous melanoma, BE.EP.DR


Cutaneous melanoma (CM) deserves prominence among malignant tumors due to its high metastatic potential and therapeutic refractoriness. The Janus kinase/Signal tranducer (JAK/STAT) signaling pathway, with the JAK1, JAK2 and STAT3 proteins, regulates the development, progression and metastatic potential of the tumor. The JAK1, JAK2 and STAT3 proteins are encoded by polymorphic genes in humans and thus it is possible for normal individuals to present inherited differences in the functionality of the JAK/STAT pathway, with consequent different risks for the occurrence of CM and different clinicopathological aspects of the tumor. The objectives of the study are to verify whether single nucleotide gene polymorphisms (SNPs) in the JAK1 gene (c.1648+1272A>G, c.991-27C>T), JAK2 (c.-1190G>T, 2428T>A) and STAT3 (c.*1671C> T, c-1697C>G) influence the risk, clinical and biological manifestations and survival of CM patients, as well as the expressions of genes and proteins. 260 patients with CM will be evaluated at Clinical Oncology and Dermatology outpatient clinics of the State University of Campinas (UNICAMP) and 260 controls, blood donors, at the Hemocentro of UNICAMP, matched by age, sex, race, and ancestry. The patients received conventional therapy with surgery, radiotherapy and chemotherapy. Genotyping will be performed by real-time polymerase chain reaction (RT-PCR). Genetic expressions of the three genes will be performed by quantitative PCR. Expressions of the three proteins will be analyzed by immunohistochemistry in paraffin embedded tumors. Gene expression and quantification of proteins of one of the SNPs of interest, those presenting an association with risk, clinical manifestations and/ or survival will be complemented by quantitative PCR and western blot, respectively, in the A-375 melanoma cell line genetically modified to present the wild homozygote and homozygous variant genotypes. It will be checked whether SNPs' loci are in Hardy-Weinberg equilibrium in patient samples and controls. The ancestry analysis will be calculated using the program STRUCTURE v 2.3.3. The statistical significance of the differences between groups will be calculated by the Fisher or chi-square test. The risks of CM occurrence, to which patients and controls were submitted, will be obtained through the odds ratios. Comparisons of gene and protein expression will be performed using the t and ANOVA or Mann-Whitney and Kruskal-Wallis tests. Survival analyzes will be calculated by Kaplan-Meier and log-rank test and Cox analyzes. We believe that the results of this study may contribute to identify individuals at high risk of tumor occurrence or of even more aggressive tumor that deserve to receive special attention in the prevention, early diagnosis or differentiated therapeutics. (AU)

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