Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

Abstract

Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2 Ã 04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P ¼ 0.01).In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P ¼ 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P ¼ 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P ¼ 0.03). Conclusions:We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

“…Yolanda Campos-Martín, 1 Nerea Martínez, 2 Azahara Martínez-López, 1 Laura Cereceda, 2 Felipe Casado,…”

Recurrent autoimmune hemolytic anemia in splenic marginal zone lymphoma

“…Hodgkin lymphoma was excluded by the absence of Reed–Sternberg cells on bone marrow histology and by flow cytometry. Although genetic testing for NOTCH2 and TP53 was not done in our patient, studies have shown that these gene mutations are independent markers of poor prognosis [6]…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…In addition, while some genes are biased to certain lymphoma entities, e.g. SF3B1 mutations in CLL, 14,15 KLF2 mutations in SMZL, [16][17][18] ID3 and TCF3 mutations in BL, 19 STAT3 mutations in large granular lymphocyte (LGL) leukemia, 11 and RHOA mutations in angioimmunoblastic T-cell lymphoma (AITL), 20,21 other genes found recurrently mutated, such as genes involved in DNA repair, epigenetic modification and regulation of transcription (Figure 1), can be detected in multiple subtypes (Table 1) and even in other cancer types.…”

“…Although they have been linked to poor clinical outcome in DLBCL, 35 SMZL 16 and MCL, 36,37 this information does not currently have any impact on treatment decisions or follow-up strategies for the individual lymphoma patient.…”

“…For instance, the MYD88 L265P mutation is detected in a significant fraction of DLBCL of the activated B-cell-like subtype (ABC DLBCL), 5 as well as in primary cutaneous, 45 the central nervous system 46 and testicular large B-cell lymphomas, 47 but also in a minority of patients with CLL 4,[48][49][50] and SMZL. 16,51 As another example, STAT3 mutations have been reported, albeit rarely, in immune, mainly hypoplastic, bone marrow failure characterizing a subset of patients with severe aplastic anemia or myelodysplastic syndrome. 52 Moreover, some gene mutations are mainly found in a specific lymphoma entity at a relatively high frequency, whereas they are rare in other subtypes, e.g.…”