Mutational patterns along different evolution paths of follicular lymphoma

Miri Michaeli, Emanuela Carlotti, Helena Hazanov, John G. Gribben, Ramit Mehr

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2 Scopus citations

Abstract

Follicular lymphoma (FL) is an indolent disease, characterized by a median life expectancy of 18-20 years and by intermittent periods of relapse and remission. FL frequently transforms into the more aggressive diffuse large B cell lymphoma (t-FL). In previous studies, the analysis of immunoglobulin heavy chain variable region (IgHV) genes in sequential biopsies from the same patient revealed two different patterns of tumor clonal evolution: direct evolution, through acquisition of additional IgHV mutations over time, or divergent evolution, in which lymphoma clones from serial biopsies independently develop from a less-mutated common progenitor cell (CPC). Our goal in this study was to characterize the somatic hypermutation (SHM) patterns of IgHV genes in sequential FL samples from the same patients, and address the question of whether the mutation mechanisms (SHM targeting, DNA repair or both), or selection forces acting on the tumor clones, were different in FL samples compared to healthy control samples, or in late relapsed/transformed FL samples compared to earlier ones. Our analysis revealed differences in the distribution of mutations from each of the nucleotides when tumor and non-tumor clones were compared, while FL and transformed FL (t-FL) tumor clones displayed similar mutation distributions. Lineage tree measurements suggested that either initial clone affinity or selection thresholds were lower in FL samples compared to controls, but similar between FL and t-FL samples. Finally, we observed that both FL and t-FL tumor clones tend to accumulate larger numbers of potential N-glycosylation sites due to the introduction of new SHM. Taken together, these results suggest that transformation into t-FL, in contrast to initial FL development, is not associated with any major changes in DNA targeting or repair, or the selection threshold of the tumor clone.

Original languageEnglish
Article number1029995
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - 10 Nov 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Michaeli, Carlotti, Hazanov, Gribben and Mehr.

Funding

This study was supported by US-Israel Binational Science Foundation (BSF) grant number 20130432 and Israel Science Foundation grant number 270/09 (to RM). MM and HH were supported by Bar-Ilan University President’s PhD Scholarships.

FundersFunder number
United States - Israel Binational Science Foundation
United States-Israel Binational Science Foundation20130432
Israel Science Foundation270/09

    Keywords

    • B lymphocytes
    • clonal evolution
    • follicular lymphoma
    • high-throughput sequencing
    • somatic hypermutation

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