TET-2 mutations predict poor outcomes and are associated with unfavorable clinical-biological features in PTCL, not otherwise specified and angioimmunoblastic T-cell lymphoma in Brazilian patients

Author(s)

de Padua Covas Lage, Luis Alberto ; Barreto, Guilherme Carneiro ; Culler, Hebert Fabricio ; Cavalcante, Jessica Billar ; de Oliveira Alves, Lucas Bassolli ; Nardinelli, Luciana ; Bendit, Israel ; Nogueira Zerbini, Maria Claudia ; Rocha, Vanderson ; Pereira, Juliana

• Document type: Journal article
• Source: CANCER BIOMARKERS; v. 35, n. 2, p. 13-pg., 2022-01-01.

Abstract

INTRODUCTION: Nodal peripheral T-cell lymphomas [nPTCL] constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation play a central role in their pathogenesis. However, the mutational landscape involving epigenetic regulators has never been reported in Latin American patients and their prognostic impact remains controversial. PATIENTS AND METHODS: From 2000 to 2019, 59-Brazilian patients with nPTCL were eligible for screening mutations in the IDH-1, IDH-2, RHOA, TET-2 and DNMT3A genes by Sanger sequencing at Formalin-Fixed Paraffin-Embedded samples [FFPE] of diagnosis. We reported the frequency, distribution and potential prognosis of these mutations. RESULTS: With a median follow-up of 3.70 years, estimate 2-year OS and PFS were 57.1% and 49.2%, respectively. Mutations in the IDH-1 gene were not found, mutations in the IDH-2 occurred in 3.4% (2/59), RHOA in 23.7% (14/59), TET-2 in 50.8% (30/59) and DNMT3A in 62.7% (37/59). RHOA gene mutations were more frequent in PTCL, NOS and AITL (p = 0.06). Almost half of the patients had more than one mutation in concomitance, particularly RHOA-mut and TET-2-mut. Mutations in RHOA (p = 0.030) and TET-2 (p = 0.046) were associated with high-tumor burden. In the non-ALCL subgroup (PTCL, NOS and AITL) TET-2 mutations were associated with decreased 2-year PFS [HR: 2.22, p = 0.048]. Likewise with lower overall response rate [ORR] (p = 0.048) and unfavorable clinical features, as bulky disease (p = 0.012), ECOG >= 2 (p = 0.032), B-symptoms (p = 0.012), >= 2 extranodal sites compromised (p = 0.022) and high-risk Prognostic Index for T-cell lymphoma (p = 0.005). CONCLUSION: Mutations in RHOA, TET-2 and DNMT3A were frequent in Brazilian patients with nPTCL. TET-2 mutations were associated with lower ORR for CHOP-like chemotherapy, decreased PFS and unfavorable clinical-biological characteristics in non-ALCL (PTCL, NOS and AITL). Further studies using a larger cohort may validate our findings. (AU)

• FAPESP's process: 12/50495-3 - Analysis of gene expression profile of cell proliferation and inflammatory response and the pattern of methylation of tumor suppressor genes p16INK4A and p15INK4b and its implications in the prognosis of peripheral T-cell lymphomas
• Grantee: Juliana Pereira
• Support Opportunities: Regular Research Grants