Molecular landscape of distinct follicular lymphoma histologic grades: insights from genomic and transcriptome analyses

The 2022 World Health Organization Classification of Haematolymphoid tumours classifies follicular lymphoma grades 1–2 (FL1-2) and grade 3A (FL3A) as classic follicular lymphoma (cFL) and reclassifies grade 3B (FL3B) as follicular large B-cell lymphoma (FLBL), without addressing cases of patients with concurrent FL and diffuse large B-cell lymphoma (FL/DLBCL). However, genetic information on FL histologic grading remains limited, and the latest classification lacks sufficient evidence to resolve whether these subgroups represent single or multiple distinct biological entities. This study analyzed clinical data from 831 patients, whole-exome sequencing (WES) from 149 patients, and transcriptome sequencing from 63 patients to explore differences among FL1-2, FL3A, FL3B, and FL/DLBCL. Clinical analyses revealed two distinct groups: an indolent group (FL1-2 and FL3A) with favorable prognosis and an aggressive group (FL3B and FL/DLBCL) characterized by poor prognosis. Genomics revealed that FL1-2 and FL3A share a common genetic background, whereas FL3B and FL/DLBCL lack mutations in epigenetic regulators CREBBP and KMT2D but exhibit additional copy number variations (CNVs), such as 1p36.32 losses and 3p21.1 gains, which are linked to poor prognosis. Transcriptomics revealed that with increasing histologic grade, immune-related pathway activity decreases, while the activity of metabolic and cell cycle pathways increases, which may be associated with the upregulation of MYC, IRF4, and BATF expression. Together, these findings define FL3B and FL/DLBCL as biologically and clinically distinct B-cell lymphomas, differing from traditional FL. FL1-2 and FL3A differ in their tumor microenvironments rather than genetic profiles.