Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing
Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing
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 re-sequencing and explored potential clinical implications in a multinational cohort of 175 SMZL patients.
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 yrs; P=0.01). In multivariate analysis mutations in NOTCH2 (HR 2.12, 95%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, while 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.
4174-4183
Parry, Marina
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Rose-Zerilli, Matthew J.
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Ljungstrom, Viktor
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Gibson, Jane
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Wang, Jun
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Parker, Helen
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Parker, A
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David, Zadie
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Gardiner, Anne
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McIver-Brown, Neil
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Kalpadakis, Christina
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Xochelli, Aliki
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Anagnostopoulos, Achilles
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Fazi, Claudia
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Gonzalez de Castro, David
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Dearden, Claire
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Pratt, Guy
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Rosenquist, Richard
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Ashton-Key, Margaret
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Forconi, Francesco
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Collins, Andrew R.
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Ghia, Paolo
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Matutes, Estella
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Pangalis, Gerassimos
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Stamatopoulos, Kostas
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Oscier, David G.
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Strefford, Jonathan C.
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15 September 2015
Parry, Marina
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Rose-Zerilli, Matthew J.
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Ljungstrom, Viktor
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Gibson, Jane
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Wang, Jun
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Walewska, Renata
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Parker, Helen
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Parker, A
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David, Zadie
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Gardiner, Anne
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McIver-Brown, Neil
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Kalpadakis, Christina
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Xochelli, Aliki
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Anagnostopoulos, Achilles
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Fazi, Claudia
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Gonzalez de Castro, David
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Dearden, Claire
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Pratt, Guy
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Rosenquist, Richard
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Ashton-Key, Margaret
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Forconi, Francesco
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Collins, Andrew R.
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Ghia, Paolo
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Matutes, Estella
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Pangalis, Gerassimos
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Stamatopoulos, Kostas
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Oscier, David G.
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Strefford, Jonathan C.
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