Follicular lymphoma (FL), the second most common form of non-Hodgkin lymphoma, is a largely incurable disease of B cells, yet in many cases, because of its indolent nature, survival can extend to well beyond 10 years following diagnosis. Yet in a small number of cases, histological transformation - where fast-growing cells outnumber the smaller, slow-growing cells - or early progression to aggressive lymphoma occurs. The events leading to this increased and early mortality are poorly understood. In a study published in PLOS Medicine, Sohrab Shah and colleagues from the BC Cancer Agency in Vancouver, Canada, investigate the molecular events underlying transformation and progression and show that disparate evolutionary trajectories and mutational profiles drive these two distinct clinical endpoints.
Using whole genome sequencing, the authors analyse the genome sequence of tumours and matched normal specimens from 41 patients and classify them according to their clinical endpoints: 1) patients who presented with transformation, 2) patients who experienced tumor progression within 2.5 years after starting treatment, without evidence of transformation, 3) and those who had neither transformation nor progression up to 5 years post-diagnosis. In addition, the authors use targeted capture sequencing of known follicular lymphoma associated genes in a larger cohort of 277 patients to investigate discrete genetic events that drive transformation and early progression.
The authors show that tumors that progress early evolve in different ways than those that transform. Assessing mutations at two time points and following treatment they show that for tumours that transform, the cells or clones which constitute the majority of the aggressive tumour were extremely rare at diagnosis, if at all present. In contrast, for early progressive disease the clonal architecture remains similar from the time of diagnosis to relapse, indicating that the diagnostic tumour may already contain the properties that confer resistance to treatment. Analysis of the larger cohort pinpointed key genes and biological processes that were associated with transformation and progression.
These findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.
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Funding:
This study was supported by a Program Project Grant from the Terry Fox Research Institute, Grant No. 1023) to SS, MM, RDG, CS and JC. We also wish to acknowledge generous long term funding support from the BC Cancer Foundation. SS is supported by a Canada Research Chair and a Michael Smith Foundation for Health Research, MSFHR scholar award. RK was supported by a Postdoctoral Trainee Fellowship Award from MSFHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests:
I have read the journal's policy and the authors of this manuscript have the following competing interests: SPS is a founder and shareholder of Contextual Genomics Inc., developer of clinical genomic tests for cancer.
Citation:
Kridel R, Chan FC, Mottok A, Boyle M, Farinha P, Tan K, et al. (2016) Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study. PLoS Med 13(12): e1002197. doi:10.1371/journal.pmed.1002197
Author Affiliations:
Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada
Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada
Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
Jewish General Hospital, Montreal, Quebec, Canada
Translational Cell and Tissue Research Lab, Department for Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium
Department of Pathology, Universitaire Ziekenhuizen Leuven (UZ Leuven), Leuven, Belgium
Department of Laboratory and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
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PLoS Medicine