Tumor mutation burden involving epigenetic regulatory genes and the RhoA GTPase predicts overall survival in nodal mature T-cell lymphomas

Abstract

Nodal mature T-cell lymphomas (nMTCL) comprises a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena, including mutations in genes that control DNA methylation and histone deacetylation, in addition to inactivating mutations in the RhoA GTPase, play a central role in its pathogenesis and constitute potential new targets for therapeutic intervention. Tumor mutational burden (TMB) reflects the process of clonal evolution, predicts response to anti-cancer therapies and has emerged as a prognostic biomarker in several solid neoplasms; however, its potential prognostic impact remains unknown in nMTCL. In this study, we conducted Sanger sequencing of formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples using a target-panel to search for recurrent mutations involving the IDH-1/IDH-2, TET-2, DNMT3A and RhoA genes in 59 cases of nMTCL. For the first time, we demonstrated that high-TMB, defined by the presence of ≥ two mutations involving the aforementioned genes, was associated with decreased overall survival in nMTCL patients treated with CHOP-like regimens. Additionally, high-TMB was correlated with bulky disease, lower overall response rate, and higher mortality. Future studies using larger cohorts may validate our preliminary results that indicate TMB as a potential molecular biomarker associated with adverse prognosis in nMTCL.

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances

“…Although TET-2 mutations are considered secondary events in nMTCL-TFH-phenotype, different studies demonstrate an association of TET-2 and RhoA G17V mutations in these neoplasms, suggesting a biological cooperation between both mutations to promote AITL development ( 49 , 65 ). Recently, our research group demonstrated a high-rate of co-occurrence between TET-2 and RhoA mutations in Brazilian patients with non-anaplastic nMTCL, confirming the data found in previous experimental studies ( 51 , 52 ). In our population, composed of 59 patients with nMTCL, the RhoA -mut/ TET-2 -mut association was demonstrated in 42.8% of cases with nMTCL-TFH-phenotype, also being associated with a high-tumor volume represented by bulky disease ≥ 7 cm and decreased overall response rates (ORR) to primary treatment based on anthracyclines ( 51 ).…”

“…Mutant RhoA protein (RhoA-mut) has compromised GTP binding, which leads to alterations in the RhoA signaling pathway and impairment of its biological functions ( 24 , 50 ). The RhoA G17V mutation, associated with loss of GTPase function, is recurrently found in up to 60-70% of AITL cases, and is currently considered a diagnostic biomarker for nMTCL-TFH-phenotype ( 24 , 25 , 50 – 52 ). Recent studies using animal models point to a clear relationship between the RhoA G17V mutation and TFH-cell differentiation, establishing a pathogenic link between this molecular alteration and AITL development ( 49 , 53 , 54 ).…”

“…Laboratory and molecular-genetic biomarkers have emerged in recent decades as methods for predicting prognosis in several hematological malignancies, including AITL. Therefore, high peripheral monocyte count at diagnosis, thrombocytopenia, high-levels of immunoglobulin A (IgA), serum albumin < 35 g/L, high-levels of β2-microglobulin, reduced lymphocyte/monocyte ratio, presence of TET-2 mutations in diagnostic biopsies, the RhoA G17V mutation, high tumor mutational burden (TMB) involving a gene panel composed by the RhoA GTPase and epigenetic regulators genes ( IDH-2 , TET-2 and DNMT3A ), gene signature pattern related to monocytes and TP53 , as well as tumor status for EBV assessed by EBER-ISH in lymph nodes (EBER-negative status) adversely impacted the survival of AITL patients according to data published by different research groups in the last ten years ( 51 , 52 , 104 – 109 ).…”

Perspectives for next generation sequencing in patients with follicular lymphoma

“…Таким образом, нами был определен алгоритм расчета TMB у пациентов с ФЛ и доказана ее прогностическая значимость. В от личие от ранее опубликованных исследований [27,28], Note. Code -disease coding according to the Unified Language of Medical Systems (UMLS); n -number of genes from the studied list associated with the disease; % -the proportion of genes associated with the disease from the total number of genes from the studied list.…”