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Influence of variants in genes of inflammatory pathways modulated by the epidermal growth factor receptor on the risk, clinical pathological aspects and tumor microenvironment of Head and Neck Squamous Cell Carcinoma

Grant number: 22/16760-3
Support Opportunities:Regular Research Grants
Duration: September 01, 2023 - August 31, 2025
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Carmen Silvia Passos Lima
Grantee:Carmen Silvia Passos Lima
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Gustavo Jacob Lourenço ; José Vassallo ; Luiz Paulo Kowalski

Abstract

The epidermal growth factor receptor (EGFR) is fundamental to the proliferation of HNSCC, and EGFR inhibitors are used as therapeutic agents. EGFR activates STAT3 that leads to the production of inflammatory cytokines (IL1A, IL1B, IL32, and TNFA) and proteins (COX-2 and CCND1), responsible for development and progression of HNSCC. The roles of cancer-associated fibroblasts (CAF), cytotoxic T lymphocytes (CTL), natural killer cells (NKC), regulatory T lymphocytes (Treg) and tumor associated macrophages (TAM) of the tumor microenvironment (TM) are uncertain in the tumor. There are no studies that fully address the interactions between inflammatory proteins and MT components in CCECP. Distinct individuals exposed to environmental factors involved in CCECP present distinct risks to development of the tumor and HNSCC patients with similar clinicopathological aspects have distinct evolutions. It is possible that single-nucleotide variants (SNVs) in genes of inflammatory pathways modulated by the EGFR gene and their interactions with MT determine these differences. The roles of SNVs in the EGFR (rs2227983 and rs1050171), STAT3 (rs1053004 and rs1053023), IL1A (rs2856836), IL1B (rs1143627), IL32 (rs4786370), TNFA (rs1799724, rs1799964, and rs1800629), COX-2 (rs5275, rs20417, rs689466, and rs689470) and CCND1 (rs7177 and rs678653) genes and of inflammatory infiltrates in the tumor will be evaluated in the risk of occurrence, clinical pathological aspects, and prognosis of HNSCC patients, as well as in TM. Six hundred HNSCC patients and 600 controls will be evaluated. The genotypes will be identified in genomic DNA by real-time PCR (open array system). Infiltrates of CAFs, CTLs, NKCs, Tregs and TAMs will be evaluated by immunohistochemistry on tumor fragments in tissue microarray. The roles of ancestral and variants alleles of four SNVs of greatest interest will be assessed by flow cytometer or luciferase assays after cloning into HNSCC cell lines. Survival will be estimated by the Kaplan-Meier method and Cox regression. The results of the study may contribute to define the roles of inherited abnormalities in genes of inflammatory pathways and MT components in risk, clinicopathological aspects and prognosis of HNSCC, aiming to identify individuals at high risk for HNSCC, who deserve to receive special measures for prevention and early diagnosis of the tumor, and to identify HNSCC patients, who deserve to receive differentiated therapy. (AU)

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