Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A. Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew MungallRichard Moore, Ryan D. Morin, Nathalie A. Johnson, Laurie H. Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M. Connors, David W. Scott, Christian Steidl, Marco A. Marra, Randy D. Gascoyne, Sohrab P. Shah

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002197
JournalPLoS Medicine
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 1 2016
Externally publishedYes

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Clonal Evolution
Follicular Lymphoma
Clone Cells
Population
Genes
High-Throughput Nucleotide Sequencing
Neoplasms
Mutation
B-Lymphocytes
Therapeutics
Genome
Recurrence
Polymerase Chain Reaction
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kridel, R., Chan, F. C., Mottok, A., Boyle, M., Farinha, P., Tan, K., ... Shah, S. P. (2016). Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study. PLoS Medicine, 13(12), [e1002197]. https://doi.org/10.1371/journal.pmed.1002197

Histological Transformation and Progression in Follicular Lymphoma : A Clonal Evolution Study. / Kridel, Robert; Chan, Fong Chun; Mottok, Anja; Boyle, Merrill; Farinha, Pedro; Tan, King; Meissner, Barbara; Bashashati, Ali; McPherson, Andrew; Roth, Andrew; Shumansky, Karey; Yap, Damian; Ben-Neriah, Susana; Rosner, Jamie; Smith, Maia A.; Nielsen, Cydney; Giné, Eva; Telenius, Adele; Ennishi, Daisuke; Mungall, Andrew; Moore, Richard; Morin, Ryan D.; Johnson, Nathalie A.; Sehn, Laurie H.; Tousseyn, Thomas; Dogan, Ahmet; Connors, Joseph M.; Scott, David W.; Steidl, Christian; Marra, Marco A.; Gascoyne, Randy D.; Shah, Sohrab P.

In: PLoS Medicine, Vol. 13, No. 12, e1002197, 01.12.2016.

Research output: Contribution to journalArticle

Kridel, R, Chan, FC, Mottok, A, Boyle, M, Farinha, P, Tan, K, Meissner, B, Bashashati, A, McPherson, A, Roth, A, Shumansky, K, Yap, D, Ben-Neriah, S, Rosner, J, Smith, MA, Nielsen, C, Giné, E, Telenius, A, Ennishi, D, Mungall, A, Moore, R, Morin, RD, Johnson, NA, Sehn, LH, Tousseyn, T, Dogan, A, Connors, JM, Scott, DW, Steidl, C, Marra, MA, Gascoyne, RD & Shah, SP 2016, 'Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study', PLoS Medicine, vol. 13, no. 12, e1002197. https://doi.org/10.1371/journal.pmed.1002197
Kridel, Robert ; Chan, Fong Chun ; Mottok, Anja ; Boyle, Merrill ; Farinha, Pedro ; Tan, King ; Meissner, Barbara ; Bashashati, Ali ; McPherson, Andrew ; Roth, Andrew ; Shumansky, Karey ; Yap, Damian ; Ben-Neriah, Susana ; Rosner, Jamie ; Smith, Maia A. ; Nielsen, Cydney ; Giné, Eva ; Telenius, Adele ; Ennishi, Daisuke ; Mungall, Andrew ; Moore, Richard ; Morin, Ryan D. ; Johnson, Nathalie A. ; Sehn, Laurie H. ; Tousseyn, Thomas ; Dogan, Ahmet ; Connors, Joseph M. ; Scott, David W. ; Steidl, Christian ; Marra, Marco A. ; Gascoyne, Randy D. ; Shah, Sohrab P. / Histological Transformation and Progression in Follicular Lymphoma : A Clonal Evolution Study. In: PLoS Medicine. 2016 ; Vol. 13, No. 12.
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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.",
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T2 - A Clonal Evolution Study

AU - Kridel, Robert

AU - Chan, Fong Chun

AU - Mottok, Anja

AU - Boyle, Merrill

AU - Farinha, Pedro

AU - Tan, King

AU - Meissner, Barbara

AU - Bashashati, Ali

AU - McPherson, Andrew

AU - Roth, Andrew

AU - Shumansky, Karey

AU - Yap, Damian

AU - Ben-Neriah, Susana

AU - Rosner, Jamie

AU - Smith, Maia A.

AU - Nielsen, Cydney

AU - Giné, Eva

AU - Telenius, Adele

AU - Ennishi, Daisuke

AU - Mungall, Andrew

AU - Moore, Richard

AU - Morin, Ryan D.

AU - Johnson, Nathalie A.

AU - Sehn, Laurie H.

AU - Tousseyn, Thomas

AU - Dogan, Ahmet

AU - Connors, Joseph M.

AU - Scott, David W.

AU - Steidl, Christian

AU - Marra, Marco A.

AU - Gascoyne, Randy D.

AU - Shah, Sohrab P.

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N2 - 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.

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