Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing
Year: 2015
Type: article
Study design: Observational Study
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.
Source: Clinical Cancer Research
Authors: 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, David Gonzalez de Castro, Claire Dearden, Guy Pratt, Richard Rosenquist, Margaret Ashton-Key, Francesco Forconi, Andrew Collins, Paolo Ghia, Estella Matutes, Gerassimos Pangalis, Kostas Stamatopoulos, David Oscier, Jonathan C. Strefford
Institutions: University of Southampton, Uppsala University, Science for Life Laboratory, Queen Mary University of London, Barts Cancer Institute, Royal Bournemouth Hospital, University of Crete, Centre for Research and Technology Hellas, G. Papanikolaou General Hospital, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, Institute of Cancer Research, Heart of England NHS Foundation Trust, University of Birmingham, Hospital Clínic de Barcelona, Athens Medical Center
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G3375317299, G6679978076
OpenAlex ID: W2105508736