Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing
2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 18, 4174-4183 p.Article in journal (Refereed) Published
Purpose:<bold> </bold>Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design:<bold> </bold>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*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 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 = 0.03). Conclusions:<bold> </bold>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.
Place, publisher, year, edition, pages
2015. Vol. 21, no 18, 4174-4183 p.
Cancer and Oncology Medical Genetics
IdentifiersURN: urn:nbn:se:uu:diva-267335DOI: 10.1158/1078-0432.CCR-14-2759ISI: 000363329900018PubMedID: 25779943OAI: oai:DiVA.org:uu-267335DiVA: diva2:873626
FunderSwedish Cancer SocietySwedish Research Council