Clinical cancer research : an official journal of the American Association for Cancer Research · 2015
Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Parry Marina, Rose-Zerilli Matthew Jj, Ljungström Viktor, Gibson Jane, Wang Jun, Walewska Renata, Parker Helen, Parker Anton, Davis Zadie, Gardiner Anne, McIver-Brown Neil, Kalpadakis Christina, Xochelli Aliki, Anagnostopoulos Achilles, Fazi Claudia, de Castro David Gonzalez, Dearden Claire, Pratt Guy, Rosenquist Richard, Ashton-Key Margaret, Forconi Francesco, Collins Andrew, Ghia Paolo, Matutes Estella, Pangalis Gerassimos, Stamatopoulos Kostas, Oscier David, Strefford Jonathan C
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAgedAged, 80 and overCohort StudiesDNA Mutational AnalysisDNA-Binding ProteinsFemaleGenetic MarkersHigh-Throughput Nucleotide SequencingHumansIntracellular Signaling Peptides and ProteinsKruppel-Like Transcription FactorsLymphoma, B-Cell, Marginal ZoneMaleMiddle AgedMultivariate AnalysisMutationMyeloid Differentiation Factor 88Neoplasm ProteinsNuclear ProteinsPrognosisReceptor, Notch2Risk FactorsSplenic NeoplasmsTranscription FactorsTreatment OutcomeTumor Necrosis Factor alpha-Induced Protein 3Tumor Suppressor Protein p53