Mutational patterns along different evolution paths of follicular lymphoma

Miri Michaeli; Emanuela Carlotti; Helena Hazanov; John G Gribben; Ramit Mehr

doi:10.3389/fonc.2022.1029995

Mutational patterns along different evolution paths of follicular lymphoma

Front Oncol. 2022 Nov 10:12:1029995. doi: 10.3389/fonc.2022.1029995. eCollection 2022.

Authors

Miri Michaeli¹, Emanuela Carlotti², Helena Hazanov¹, John G Gribben², Ramit Mehr¹

Affiliations

¹ The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
² Center for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.

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.

Keywords: B lymphocytes; clonal evolution; follicular lymphoma; high-throughput sequencing; somatic hypermutation.