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

Abstract

Although the genomic and immune microenvironmental 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 cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR] <0.001) were more 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) mutations were found more frequently in stage III/IV FL. Using clustering, we identified 3 clusters within stage I, and 2 clusters 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 fewer CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl– stage I cluster was relatively heterogeneous with more copy number aberrations and linker histone mutations. This exploratory study shows that stage I FL is genetically heterogeneous with different underlying oncogenic pathways. Stage I FL BCL2trl– is likely STAT6 driven, whereas BCL2trl– stage III/IV appears to be more BCL6trl driven.

Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms

“…These largely overlapping biological features of lFL and sFL are surprising given the tremendously differing prognostic impact of a diagnosis of lFL versus sFL. Our data thus con rm and extend recently published data on lFL versus sFL that already indicated a close genetic relationship of lFL and sFL with overlapping features on SCNA and mutational level (25). This is in clear contrast, however, to the differences observed between lFL and sFL on the RNA and microenvironmental levels (9,27), suggesting alternative mechanisms to be important in lFL and sFL, e.g.…”

“…Apart from these novel insights into the SCNA landscape of lFL, to the best of our knowledge, this is the rst study performing WES in lFL. The mutation-based pro les of lFL and sFL were found to be remarkably similar corroborating previous ndings in targeted sequencing approaches (25,36), as were the median numbers of mutations in each type. With only targeted NGS analyses of lFL available until now, a global view towards the landscape of mutations in lFL and sFL has not yet been provided.…”

“…Of special interest, patients with KIR3DL1 mutations show signi cantly reduced expression of NK cell activation markers CD4 (20), ITK (21) and SH2D1A (22) thus emphasizing the potential impact of KIR3DL1 mutations in the modulation of the microenvironment in lFL. KMT2D and ARID1A, modulators of chromatin remodeling processes, are more frequently mutated in sFL than in lFL, as previously published (25), possibly contributing towards altered chromatin regulation in lFL and sFL. In contrast, mutations in CREBBP were equally distributed in lFL and sFL (25).…”

The fifth edition of the WHO classification of mature B‐cell neoplasms: open questions for research

“…The t(14;18)(q32;q21) results in a BCL2 rearrangement (BCL2-R) via IGH::BCL2 juxtaposition, the genetic hallmark of FL, and is found in $85% of cases [31][32][33][34], much higher in an advanced stage (stage III/IV, 90%) than an early stage (stage I/II, 50%) FL [32,33]. The translocation drives aberrant BCL2 expression, and this prevents B cells from undergoing apoptosis and prolongs their stay in the GC and their iterative GC reactions.…”

“…Follicular lymphoma and its heterogeneous features. (A) Comparison of major genetic changes between FL with and without BCL2-R[27][28][29][30][31][32][33][34][35][36][37][38]. *Approximate frequency of alterations; some alterations may be subclonal.…”