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

Marina Parry, Matthew J.J. Rose-Zerilli, Viktor Ljungström, Jane Gibson, Jun Wang, Renata Walewska, Helen Parker, Anton Parker, Zadie Davis, Anne Gardiner, Neil McIver-Brown, Christina Kalpadakis, Aliki Xochelli, Achilles Anagnostopoulos, Claudia Fazi, D. Gonzalez de Castro, Claire Dearden, Guy Pratt, Richard Rosenquist, Margaret Ashton-KeyFrancesco Forconi, Andrew Collins, Paolo Ghia, Estella Matutes, Gerassimos Pangalis, Kostas Stamatopoulos, David Oscier, Jonathan C. Strefford

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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*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: 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.
Original languageEnglish
Pages (from-to)4174-4183
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
Publication statusPublished - Sep 2015

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    Parry, M., Rose-Zerilli, M. J. J., Ljungström, V., Gibson, J., Wang, J., Walewska, R., Parker, H., Parker, A., Davis, Z., Gardiner, A., McIver-Brown, N., Kalpadakis, C., Xochelli, A., Anagnostopoulos, A., Fazi, C., Gonzalez de Castro, D., Dearden, C., Pratt, G., Rosenquist, R., ... Strefford, J. C. (2015). Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing. Clinical Cancer Research, 21(18), 4174-4183. https://doi.org/10.1158/1078-0432.CCR-14-2759