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Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study
CR. Bolen, M. Klanova, M. Trneny, LH. Sehn, J. He, J. Tong, JN. Paulson, E. Kim, U. Vitolo, A. Di Rocco, G. Fingerle-Rowson, T. Nielsen, G. Lenz, MZ. Oestergaard
Jazyk angličtina Země Itálie
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 1994
Free Medical Journals
od 1994
Freely Accessible Science Journals
od 1994
PubMed Central
od 2009
Europe PubMed Central
od 2009
Open Access Digital Library
od 1994-01-01
ROAD: Directory of Open Access Scholarly Resources
od 1996
- MeSH
- cyklofosfamid terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * diagnóza farmakoterapie genetika MeSH
- doxorubicin terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- prednison terapeutické užití MeSH
- prognóza MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- protoonkogenní proteiny c-bcl-2 genetika MeSH
- protoonkogenní proteiny c-myc * genetika MeSH
- rituximab terapeutické užití MeSH
- vinkristin terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.
1st Department of Medicine Charles University General Hospital Prague Czech Republic
A O Universitaria Città della Salute e della Scienza di Torino Ematologia Torino Italy
Bioinformatics and Computational Biology Genentech Inc South San Francisco CA USA
British Columbia Cancer Centre for Lymphoid Cancer Vancouver Canada
Department of Biostatistics Product Development Genentech Inc South San Francisco CA USA
Department of Cellular Biotechnologies and Hematology Sapienza University Rome Italy
Department of Medicine A Hematology Oncology and Pneumology University Hospital Muenster Muenster
Foundation Medicine Inc Cambridge MA USA
Oncology Biomarker Development F Hoffmann La Roche Ltd Basel Switzerland
Pharma Development Clinical Oncology F Hoffmann La Roche Ltd Basel Switzerland
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- $a Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.
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