Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal
dynamics,” according to researchers.
The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.
Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.
The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.
The team then classified the patients according to the following clinical endpoints:
- Patients who presented with transformation (n=15)
- Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
- Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).
The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.
Results showed that tumors that progress early evolve in different ways from those that transform.
The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.
In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.
Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.
The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.
The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.
The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.
The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.
The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.
