Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report
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- Stuart E. Lacy
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom;
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- Sharon L. Barrans
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom;
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- Philip A. Beer
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;
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- Daniel Painter
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom;
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- Alexandra G. Smith
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom;
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- Eve Roman
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom;
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- Susanna L. Cooke
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;
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- Camilo Ruiz
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;
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- Paul Glover
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom;
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- Suzan J. L. Van Hoppe
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom;
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- Nichola Webster
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom;
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- Peter J. Campbell
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;
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- Reuben M. Tooze
- Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom;
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- Russell Patmore
- Queen’s Centre for Oncology and Haematology, Castle Hill Hospital, Cottingham, United Kingdom; and
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- Cathy Burton
- Haematological Malignancy Diagnostic Service, St. James’s Institute of Oncology, Leeds, United Kingdom;
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- Simon Crouch
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom;
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- Daniel J. Hodson
- Wellcome–MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
説明
<jats:title>Abstract</jats:title> <jats:p>Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.</jats:p>
収録刊行物
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- Blood
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Blood 135 (20), 1759-1771, 2020-05-14
American Society of Hematology