Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies
Abstract Background Diffuse large B-cell lymphoma (DLBCL) is a heterogenous blood cancer, but can be broadly classified into two main subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). GCB and ABC subtypes have very different clinical courses, with ABC having a much worse s...
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doaj-dd1dbd6712ab427ab6b8e4a4c9f5aa082020-11-25T02:04:21ZengBMCTranslational Medicine Communications2396-832X2020-03-015111310.1186/s41231-020-00054-1Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsiesEwan Hunter0Ronald McCord1Aroul S. Ramadass2Jayne Green3Jurjen W. Westra4Kirsten Mundt5Alexandre Akoulitchev6Oxford BioDynamics PlcGenentech Inc.Oxford BioDynamics PlcOxford BioDynamics PlcOxford BioDynamics PlcHoffmann La-Roche AGOxford BioDynamics PlcAbstract Background Diffuse large B-cell lymphoma (DLBCL) is a heterogenous blood cancer, but can be broadly classified into two main subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). GCB and ABC subtypes have very different clinical courses, with ABC having a much worse survival prognosis. It has been observed that patients with different subtypes also respond differently to therapeutic intervention, in fact, some have argued that ABC and GCB can be thought of as separate diseases altogether. Due to this variability in response to therapy, having an assay to determine DLBCL subtypes has important implications in guiding the clinical approach to the use of existing therapies, as well as in the development of new drugs. The current gold standard assay for subtyping DLBCL uses gene expression profiling on formalin fixed, paraffin embedded (FFPE) tissue to determine the “cell of origin” and thus disease subtype. However, this approach has some significant clinical limitations in that it 1) requires a biopsy 2) requires a complex, expensive and time-consuming analytical approach and 3) does not classify all DLBCL patients. Methods Here, we took an epigenomic approach and developed a blood-based chromosome conformation signature (CCS) for identifying DLBCL subtypes. An iterative approach using clinical samples from 118 DLBCL patients was taken to define a panel of six markers (DLBCL-CCS) to subtype the disease. The performance of the DLBCL-CCS was then compared to conventional gene expression profiling (GEX) from FFPE tissue. Results The DLBCL-CCS was accurate in classifying ABC and GCB in samples of known status, providing an identical call in 100% (60/60) samples in the discovery cohort used to develop the classifier. Also, in the assessment cohort the DLBCL-CCS was able to make a DLBCL subtype call in 100% (58/58) of samples with intermediate subtypes (Type III) as defined by GEX analysis. Most importantly, when these patients were followed longitudinally throughout the course of their disease, the EpiSwitch™ associated calls tracked better with the known patterns of survival rates for ABC and GCB subtypes. Conclusion This proof-of-concept study provides an initial indication that a simple, accurate, cost-effective and clinically adoptable blood-based diagnostic for identifying DLBCL subtypes is possible.http://link.springer.com/article/10.1186/s41231-020-00054-1Diffuse large B-cell lymphoma (DLBCL)Disease subtypeEpigeneticsGene expressionChromatin conformation signatures (CCS) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ewan Hunter Ronald McCord Aroul S. Ramadass Jayne Green Jurjen W. Westra Kirsten Mundt Alexandre Akoulitchev |
spellingShingle |
Ewan Hunter Ronald McCord Aroul S. Ramadass Jayne Green Jurjen W. Westra Kirsten Mundt Alexandre Akoulitchev Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies Translational Medicine Communications Diffuse large B-cell lymphoma (DLBCL) Disease subtype Epigenetics Gene expression Chromatin conformation signatures (CCS) |
author_facet |
Ewan Hunter Ronald McCord Aroul S. Ramadass Jayne Green Jurjen W. Westra Kirsten Mundt Alexandre Akoulitchev |
author_sort |
Ewan Hunter |
title |
Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies |
title_short |
Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies |
title_full |
Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies |
title_fullStr |
Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies |
title_full_unstemmed |
Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies |
title_sort |
comparative molecular cell-of-origin classification of diffuse large b-cell lymphoma based on liquid and tissue biopsies |
publisher |
BMC |
series |
Translational Medicine Communications |
issn |
2396-832X |
publishDate |
2020-03-01 |
description |
Abstract Background Diffuse large B-cell lymphoma (DLBCL) is a heterogenous blood cancer, but can be broadly classified into two main subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). GCB and ABC subtypes have very different clinical courses, with ABC having a much worse survival prognosis. It has been observed that patients with different subtypes also respond differently to therapeutic intervention, in fact, some have argued that ABC and GCB can be thought of as separate diseases altogether. Due to this variability in response to therapy, having an assay to determine DLBCL subtypes has important implications in guiding the clinical approach to the use of existing therapies, as well as in the development of new drugs. The current gold standard assay for subtyping DLBCL uses gene expression profiling on formalin fixed, paraffin embedded (FFPE) tissue to determine the “cell of origin” and thus disease subtype. However, this approach has some significant clinical limitations in that it 1) requires a biopsy 2) requires a complex, expensive and time-consuming analytical approach and 3) does not classify all DLBCL patients. Methods Here, we took an epigenomic approach and developed a blood-based chromosome conformation signature (CCS) for identifying DLBCL subtypes. An iterative approach using clinical samples from 118 DLBCL patients was taken to define a panel of six markers (DLBCL-CCS) to subtype the disease. The performance of the DLBCL-CCS was then compared to conventional gene expression profiling (GEX) from FFPE tissue. Results The DLBCL-CCS was accurate in classifying ABC and GCB in samples of known status, providing an identical call in 100% (60/60) samples in the discovery cohort used to develop the classifier. Also, in the assessment cohort the DLBCL-CCS was able to make a DLBCL subtype call in 100% (58/58) of samples with intermediate subtypes (Type III) as defined by GEX analysis. Most importantly, when these patients were followed longitudinally throughout the course of their disease, the EpiSwitch™ associated calls tracked better with the known patterns of survival rates for ABC and GCB subtypes. Conclusion This proof-of-concept study provides an initial indication that a simple, accurate, cost-effective and clinically adoptable blood-based diagnostic for identifying DLBCL subtypes is possible. |
topic |
Diffuse large B-cell lymphoma (DLBCL) Disease subtype Epigenetics Gene expression Chromatin conformation signatures (CCS) |
url |
http://link.springer.com/article/10.1186/s41231-020-00054-1 |
work_keys_str_mv |
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