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Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing
Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Univ Southampton, Ctr Biol Sci, Southampton, Hants, England..
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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
Abstract [en]

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.
National Category
Cancer and Oncology Medical Genetics
URN: urn:nbn:se:uu:diva-267335DOI: 10.1158/1078-0432.CCR-14-2759ISI: 000363329900018PubMedID: 25779943OAI: oai:DiVA.org:uu-267335DiVA: diva2:873626
Swedish Cancer SocietySwedish Research Council
Available from: 2015-11-24 Created: 2015-11-20 Last updated: 2015-11-24Bibliographically approved

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