TY - JOUR
T1 - Genetics and prognostication in splenic marginal zone lymphoma
T2 - Revelations from deep sequencing
AU - Parry, Marina
AU - Rose-Zerilli, Matthew J J
AU - Ljungström, Viktor
AU - Gibson, Jane
AU - Wang, Jun
AU - Walewska, Renata
AU - Parker, Helen
AU - Parker, Anton
AU - Davis, Zadie
AU - Gardiner, Anne
AU - McIver-Brown, Neil
AU - Kalpadakis, Christina
AU - Xochelli, Aliki
AU - Anagnostopoulos, Achilles
AU - Fazi, Claudia
AU - De Castro, David Gonzalez
AU - Dearden, Claire
AU - Pratt, Guy
AU - Rosenquist, Richard
AU - Ashton-Key, Margaret
AU - Forconi, Francesco
AU - Collins, Andrew
AU - Ghia, Paolo
AU - Matutes, Estella
AU - Pangalis, Gerassimos
AU - Stamatopoulos, Kostas
AU - Oscier, David
AU - Strefford, Jonathan C.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-14-2759
DO - 10.1158/1078-0432.CCR-14-2759
M3 - Article
AN - SCOPUS:84942742967
VL - 21
SP - 4174
EP - 4183
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 18
ER -