Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns

Area of Science:

• Hematology
• Genomics
• Oncology

Background:

• Follicular lymphoma (FL) represents about 20% of new lymphoma cases.
• Histologic transformation (HT) to diffuse large B-cell lymphoma (DLBCL) affects up to 15% of FL patients.
• Predictive genetic markers for FL progression and HT are not well-established.

Purpose of the Study:

• To analyze mutation landscapes in FL and DLBCL using whole-genome sequencing.
• To identify distinct genetic subgroups within FL.
• To develop a classification approach for predicting HT risk.

Main Methods:

• Whole-genome sequencing of 423 patients with untransformed FL, transformed FL, and de novo DLBCL.
• Comparative analysis of protein coding and noncoding mutation landscapes.
• Machine learning-based classification to stratify FL into subgroups.

Main Results:

• Discovery of two genetically distinct FL subgroups: DLBCL-like (dFL) and constrained FL (cFL).
• Identification of unique mutational patterns and aberrant somatic hypermutation rates for each subgroup.
• Validation that cFL status is associated with a reduced rate of histologic transformation.

Conclusions:

• FL comprises at least two biologically distinct subgroups with different evolutionary potentials.
• The cFL subgroup exhibits constrained evolution, suggesting a lower risk of transformation.
• Genomic classification of FL into cFL and dFL may predict the risk of HT at diagnosis.