Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV

Although the genomic and immunemicroenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I caseswere analyzed and comparedwith 139 FL stage III/IV nodal cases.Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populationswere detected. However, therewere also significant differences inmicroenvironmental and genomic features. CD8- T cells (P= .02) and STAT6 mutations (false discovery rate [FDR],0.001)weremore frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68-/CD163- macrophages (P<.001), BCL2 translocation (BCL2trl-) (P< .0001), and KMT2D (FDR= 0.003) and CREBBP (FDR= 0.04) mutationswere foundmore frequently in stage III/IV FL. Using clustering,we identified 3 clusters within stage I, and 2 clusterswithin stage III/IV. The BLC2trl- stage I clusterwas 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%) andSTAT6 (64%)mutations,without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%)with fewer CREBBP (45%) andSTAT6 (9%)mutations. The other BCL2trl- stage I clusterwas relatively heterogeneouswith more copy number aberrations and linker histonemutations. This exploratory study shows that stage I FL is genetically heterogeneouswith different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven,whereas BCL2trl- stage III/IV appears to bemore BCL6trl driven.