Gene, protein expression and tumor necrosis factor-a (TNF-a) polymorphisms in extranodal T/NK cell lymphoma, nasal type: clinical-prognostic associations

• Grant number: 23/06928-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2023
• End date: June 30, 2024
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Luís Alberto de Pádua Covas Lage
• Grantee: Lucas Grezzi Baptista
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Extranodal T/NK cell lymphoma, nasal type (LETNKn) is a rare lymphoid malignancy derived from monoclonal proliferation of CD8+ cytotoxic T lymphocytes or natural killer (NK) cells associated with EBV infection. After infecting T/NK cells, viral oncoproteins stimulate the constitutive activation of different intracellular signaling pathways, such as AKT, JAK/STAT, MAPK and NF-kB, inhibiting apoptosis, promoting cell proliferation and modulating the immune response, thus regulating the interaction between the tumor compartment and the non-neoplastic immune microenvironment. Additionally, the LMP-1 protein promotes great genomic instability, inducing mutations and copy number changes in several oncogenes, such as those located on chromosome 6q21-q25. Among the tumor suppressor genes located in the 6q21-q25 region that are inactivated in LETNKn, FOXO3 and PRDM1 stand out. FOXO3 is a forkhead family transcriptional factor implicated in induction of apoptosis and cell cycle arrest in NK cells, while PRDM1 regulates NK activation and maturation. Mutations affecting the RAS-MAPK pathway genes are seen in 15% of LETNKn cases, commonly affecting the MAP3K5, BRAF and EPH1A genes, as well as NF-kB pathway activating mutations involving the ECSIT, IKBKB and BIRC3 genes. Although it is a rare tumor, LETNKn has a peculiar geographic distribution, being considered an endemic malignancy in South America, with a particularly high prevalence in Brazil. Therefore, the objective of this research is to demonstrate the presence of overexpression of the TNF-a gene and its respective protein in LETNKn in relation to the non-neoplastic sinus mucosa. We also hope to correlate TNF-a gene and protein overexpression and its gene polymorphisms with more aggressive clinical phenotypes and worse clinical outcomes in LETNKn. Therefore, we intend to demonstrate that TNF-a can be a potential prognostic biomarker and therapeutic target to be explored in this neoplasm.