Genetic and immunohistochemical profiling of NK/T-cell lymphomas reveals prognostically relevant BCOR-MYC association

Abstract

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an Epstein-Barr virus-positive, aggressive lymphoma, with a heterogeneous cell of origin and variable clinical course. Several clinical prognostic indices have been proposed for ENKTL; however, there are few pathological biomarkers. This multi-institutional study sought to identify histologically assessable prognostic factors. We investigated mutation profiles by targeted next-generation sequencing and immunohistochemical assessments of expression of MYC, Tyr705-phosphorylated (p-)STAT3, and CD30 in 71 ENKTL samples. The median age of the patients was 66 years (range 6-100) years. The most frequent mutations were in STAT3 (27%), JAK3 (4%), KMT2D (19%), TP53 (13%), BCOR (10%), and DDX3X (7%). Immunohistochemistry revealed that ENKTLs with STAT3 mutations exhibited higher expression of pSTAT3 and CD30. BCOR mutations were associated with increased MYC expression. Univariate analysis in the entire cohort showed that stage (II/III/IV), BCOR mutations, TP53 mutations, and high MYC expression (defined as ≥40% positive neoplastic cells) were associated with reduced overall survival. Multivariate modeling identified stage (2/3/4) and high MYC expression as independent adverse prognostic factors. In a subgroup analysis of patients treated with anthracycline-free chemotherapy and/or radiotherapy with curative intent, BCOR but not high MYC expression was an independent adverse prognostic factor. In conclusion, activating STAT3 mutations are common in ENKTLs and are associated with increased CD30 expression. MYC overexpression is, at least in part, associated with deleterious BCOR mutations, and this BCOR-MYC linkage may have prognostic significance, underscoring the potential utility of immunohistochemistry for MYC in risk stratification of patients with ENKTL.

Extranodal lymphoma: pathogenesis, diagnosis and treatment

“…The JAK/STAT pathway also plays a significant role for the development of NKTCL-NT. Mutations in the STAT3 gene are commonly observed in NKTCL-NT [ 98 ]. Activation of STAT3 is significantly correlated with the expression of programmed cell death-ligand 1 (PD-L1), suggesting that STAT3 activation leads to increased PD-L1 expression, promoting immune evasion by the tumor [ 99 ].…”

Novel target and treatment agents for natural killer/T-cell lymphoma

“…CD30 is expressed on activated lymphocytes and can mediate multiple signaling pathways to modulate cell growth, proliferation and apoptosis [ 18 ]. CD30 is expressed in 40–75% of NKTCL patients [ 19 – 21 ]. Brentuximab vedotin (BV) is an ADC that combines an anti-CD30 mAb with monomethyl auristatin E, a microtubule-targeting cytotoxic agent, and has been studied in a variety of NHLs and demonstrated satisfactory efficacy and safety [ 22 ].…”

“…NKTCL cells with mutations in JAK3 and STAT3 are more susceptible than wild-type controls to treatment with tofacitinib and stattic, respectively [ 88 ]. Patients with STAT3 mutation tend to have high expression of CD30 [ 21 ], suggesting that combining JAK/STATs inhibitors with an anti-CD30 antibody may be more effective. Two trials are currently ongoing to evaluate JAK inhibitors, tofacitinib in one trial (NCT03598959) and ruxolitinib in another (NCT02974647) in patients with r/r NKTCL.…”