While the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known regarding potential biological differences between stage I and stage III/IV disease. Using next generation sequencing (NGS) and immunohistochemistry, 82 FL nodal stage I cases were analysed and compared to 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations (CNAs) and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T-cells (p=0.02) and STAT6 mutations (FDR<0.001), were more frequent in stage I FL. In contrast, PD1+ T-cells, CD68+/CD163+ macrophages (p<0.001), BCL2 translocation (BCL2trl+) (p<0.0001), KMT2D (FDR=0.003) and CREBBP (FDR=0.04) mutations were found more frequently in stage III/IV FL. By clustering we identified three clusters within stage I, and two within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with less CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more CNAs and linker histone mutations. This exploratory study shows that FL stage I is genetically heterogenous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven while BCL2trl- stage III/IV appears to be more BCL6trl driven.
View details for DOI 10.1182/bloodadvances.2022008355
View details for PubMedID 35816682