Department of Hematology, Hemotherapy and Cell Therapy, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology, University of São Paulo (USP), São Paulo, SP, Brazil.
Cancer Biomark. 2022;35(2):179-191. doi: 10.3233/CBM-220013.
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.
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.
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).
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.
结外外周 T 细胞淋巴瘤（nPTCL）是一组具有侵袭性生物学行为和不良预后的罕见恶性肿瘤。涉及控制 DNA 甲基化和组蛋白去乙酰化的基因的表观遗传现象在其发病机制中起着核心作用。然而，涉及表观遗传调节剂的突变体图谱在拉丁美洲患者中从未报道过，其预后影响仍存在争议。
2000 年至 2019 年，59 例巴西 nPTCL 患者符合筛选诊断时福尔马林固定石蜡包埋（FFPE）样本中 IDH-1、IDH-2、RHOA、TET-2 和 DNMT3A 基因突变的条件，采用 Sanger 测序。我们报告了这些突变的频率、分布和潜在预后。
中位随访 3.70 年，估计 2 年 OS 和 PFS 分别为 57.1%和 49.2%。未发现 IDH-1 基因突变，IDH-2 突变发生在 3.4%（2/59），RHOA 突变发生在 23.7%（14/59），TET-2 突变发生在 50.8%（30/59），DNMT3A 突变发生在 62.7%（37/59）。RHOA 基因突变在 PTCL、NOS 和 AITL 中更为常见（p=0.06）。几乎一半的患者同时存在多种突变，尤其是 RHOA 突变和 TET-2 突变。RHOA（p=0.030）和 TET-2（p=0.046）突变与高肿瘤负荷相关。在非 ALCL 亚组（PTCL、NOS 和 AITL）中，TET-2 突变与 2 年 PFS 降低相关[HR：2.22，p=0.048]。同样，总反应率[ORR]较低（p=0.048），临床特征不佳，如肿块性疾病（p=0.012）、ECOG ⩾2（p=0.032）、B 症状（p=0.012）、受累 ⩾2 个结外部位（p=0.022）和高风险 T 细胞淋巴瘤预后指数（p=0.005）。
在巴西 nPTCL 患者中，RHOA、TET-2 和 DNMT3A 突变较为常见。TET-2 突变与 CHOP 样化疗的低 ORR、非 ALCL（PTCL、NOS 和 AITL）患者的 PFS 降低和不良临床生物学特征相关。进一步使用更大队列的研究可能会验证我们的发现。
