title: Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.
abstract: BACKGROUND
  Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.
  
  
  RESULTS
  Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.
  
  
  CONCLUSIONS
  Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0003-0287-7124
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authors.lastname: Kridel
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.|Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.lastname: Mottok
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Merrill
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0001-9364-9391
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authors.lastname: Farinha
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.lastname: Meissner
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0002-5654-5101
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authors.affiliation: Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0001-7196-0154
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authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0002-6901-5126
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.affiliation: 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.
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authors.initials: RD
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authors.affiliation: Jewish General Hospital, Montreal, Quebec, Canada.
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authors.identifier: http://orcid.org/0000-0002-3211-9722
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.initials: LH
authors.lastname: Sehn
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: 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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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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authors.initials: RD
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authors.affiliation: 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.
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mesh_terms: D060965:Clonal Evolution; D002999:Clone Cells; D018450:Disease Progression; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation