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

Article type: Research Article

Authors: de Pádua Covas Lage, Luís Alberto^{a; b; *} | Barreto, Guilherme Carneiro^a | Culler, Hebert Fabricio^{a; b} | Cavalcante, Jéssica Billar^b | de Oliveira Alves, Lucas Bassolli^a | Nardinelli, Luciana^{a; b} | Bendit, Israel^{a; b} | Zerbini, Maria Cláudia Nogueira^c | Rocha, Vanderson^{a; b; d; e} | Pereira, Juliana^{a; b}

Affiliations: [a] Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil | [b] Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology, University of São Paulo (USP), São Paulo, SP, Brazil | [c] Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil | [d] Fundação Pró-Sangue, Blood Bank of São Paulo, São Paulo, SP, Brazil | [e] Churchill Hospital, Oxford University, Oxford, UK

Correspondence: [*] Corresponding author: Luís Alberto de Pádua Covas Lage, Avenue Dr. Enéas de Carvalho Aguiar, 155 – Ambulatory Building of Hospital das Clínicas da Universidade de São Paulo (HC-FMUSP) – 1st. Floor, Room 61, São Paulo, Cerqueira César – SP. Zip code: 05403-000, Brazil. Tel.: +55 11 99925-7113 or +55 11 4229-9531; E-mails: [email protected] or [email protected].

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.

Keywords: Nodal peripheral T-cell lymphomas, epigenetics, mutation, mutation, biomarkers, prognosis

DOI: 10.3233/CBM-220013

Journal: Cancer Biomarkers, vol. 35, no. 2, pp. 179-191, 2022