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 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.

The Prospective Study of Epigenetic Regulatory Profiles in Sport and Exercise Monitored Through Chromosome Conformation Signatures

“…Chromosome conformation signatures (CCSs) are collections of multiple DNA contacts associated with specific functional outcomes such as disease states and gene expression patterns [ 29 ], and technologies for identifying such signatures have also been developed. Recently, an approach with a focus on clinical and industrial scale screening and applications was developed [ 39 , 40 , 41 , 42 ]. Like the original 3C methodology, EpiSwitch™ detects the absence or presence of interactions between two sites in the genome.…”

“…Recent evidence that transcription factor activity, in particular, is affected by promoter region interactions [ 21 , 47 ] demonstrates the permissiveness of CCSs to facilitate acute and persistent physiological alterations. Recent application of CCSs [ 39 , 40 ] has shown that this biomarker modality can be applied to whole blood samples [ 41 ] to provide stable, binary readouts between two states (pre-intervention vs. post-intervention, disease vs. non-diseased) based on the presence or absence of a signature [ 29 , 39 , 42 ]. It is important to note that study of CCSs requires consideration of participants individually, as opposed to their contribution to a collective group mean.…”

“…The potential of CCS has emerged in the last decade, with a number of human studies in medicine demonstrating promising results [ 39 , 40 , 41 , 42 , 50 ]. An intriguing advantage is that CCSs can indicate the likelihood that a specific condition or disease is present [ 39 , 40 ], or can be used to identify individuals who are likely to be responsive or non-responsive to medical intervention [ 41 ].…”

“…An intriguing advantage is that CCSs can indicate the likelihood that a specific condition or disease is present [ 39 , 40 ], or can be used to identify individuals who are likely to be responsive or non-responsive to medical intervention [ 41 ]. Importantly, the diagnostic concepts of sensitivity and specificity are common to each approach, describing the ability of a test to identify those with or without a given disease or trait [ 42 , 51 ]. Although sport and exercise scientists do not typically investigate disease or therapeutic intervention, medical research provides valuable insight into the potential use of CCS in exercise-related settings as part of a move towards more targeted approaches and personalised interventions.…”

3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

“…Individuals with severe disease have higher levels of circulating inflammatory mediators conformation capture (3C) methodology [20,21] that has been translated to practice for the discovery of blood-based 3D genomic biomarkers and for patient stratification. To date, 3D genomic biomarkers based on EpiSwitch ® technology have been used to successfully stratify melanoma patients, prognostically stratify patients with fast and slow progressing motor neurone disease, stratify patients with symptomatic and pre-symptomatic Huntington's disease, diagnose patients with thyroid cancer and various stages of prostate cancer, prognostically stratify patients for treatment in diffuse large B cell lymphoma, and predictively stratify patients with non-small cell lung cancer for response to the PD-L1 immuno-checkpoint inhibitor, avelumab [22][23][24][25][26][27][28][29][30].…”