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Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study
- Source :
- PLoS Medicine, Vol 13, Iss 12, p e1002197 (2016), PLoS Medicine, DOAJ-Articles, PubMed Central
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
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. Methods and Findings 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.<br />Sohrab Shah and colleagues explore the evolutionary histories that shape clinical and transformation dynamics in follicular lymphoma<br />Author Summary Why Was This Study Done? Follicular lymphoma (FL) is a largely incurable malignancy in which early progression and transformation have consistently been linked to lymphoma-related mortality. We contended that detailed characterization of clonal dynamics would reveal fundamental biological properties with implications for future patient management strategies relating to both transformation and progression. We also sought to identify recurrent gene mutations associated with transformation and/or early progression in a large patient cohort. What Did the Researchers Do and Find? Using whole genome sequencing, deep allelic sampling by amplicon sequencing, and digital droplet PCR, we found dramatic clonal expansions in transformed disease, whereby dominant clones in transformation samples emerged from extremely low prevalence clones or from clones that were not detected in the diagnostic samples. The dynamics of disease progression during treatment in the absence of transformation showed markedly different characteristics, with much of the clonal architecture preserved from diagnostic to relapse specimens. Targeted capture-based sequencing in a large extension cohort then established genetic variants associated with transformation and early progression in the broader patient population. What Do These Findings Mean? Taken together, our findings illuminate previously undescribed patterns of clonal expansion underpinning FL clinical histories suggesting that contrasting management strategies will be necessary across the FL patient population. We uncovered novel associations of gene mutations with early progression that could inform future prognostic assay development.
- Subjects :
- 0301 basic medicine
Pathology
Follicular lymphoma
medicine.disease_cause
Somatic evolution in cancer
Hematologic Cancers and Related Disorders
0302 clinical medicine
Medicine and Health Sciences
Genome Sequencing
Lymphoma, Follicular
Data Management
Mutation
Hematology
General Medicine
Phylogenetics
Oncology
030220 oncology & carcinogenesis
Disease Progression
Medicine
Lymphomas
Research Article
Computer and Information Sciences
medicine.medical_specialty
Follicular Lymphoma
Context (language use)
Biology
Research and Analysis Methods
Deep sequencing
Clonal Evolution
03 medical and health sciences
Germline mutation
Diagnostic Medicine
Genetics
Cancer Detection and Diagnosis
medicine
Humans
Evolutionary Systematics
Molecular Biology Techniques
Sequencing Techniques
Molecular Biology
Taxonomy
Evolutionary Biology
Cancers and Neoplasms
Biology and Life Sciences
medicine.disease
Clone Cells
Lymphoma
030104 developmental biology
Somatic Mutation
Progressive disease
Cloning
Subjects
Details
- Language :
- English
- ISSN :
- 15491676 and 15491277
- Volume :
- 13
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS Medicine
- Accession number :
- edsair.doi.dedup.....feaf3cbbfc25a216ac10d0980b8dbff8