Bcl-2-negative IGH-BCL2 translocation-negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl-2-positive IGH-BCL2 translocation-positive follicular lymphoma

Aims Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl-2 expression and IGH-BCL2 translocation. The clinicopathological features exhibited by Bcl-2-negative IGH-BCL2 translocation-negative FL of the thyroid (Bcl-2(-)/IGH-BCL2(-) tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl-2(-)/IGH-BCL2(-) tFL to investigate their epigenetic and genetic aberrations. Methods and results The immunohistochemical profiles of epigenetic modifiers and the methylation status of histones were examined, including EZH2, MLL2/KMT2D, CBP/CREBBP, EP300, H3K27me3 and H3K4me3, in Bcl-2(-)/IGH-BCL2(-) tFL and Bcl-2-positive IGH-BCL2 translocation-positive FL of the thyroid (Bcl-2(+)/IGH-BCL2(+) tFL). Most Bcl-2(-)/IGH-BCL2(-) tFLs retained the positivity of epigenetic modifiers and lower expression of H3K27me3, although Bcl-2(+)/IGH-BCL2(+) tFLs exhibited aberrant immunohistochemical patterns of EZH2 and CBP/CREBBP and overexpression of H3K27me3. Samples from seven cases were further analysed using targeted sequencing, focusing on the exons of 409 key tumour suppressor genes and oncogenes. Bcl-2(-)/IGH-BCL2(-) tFLs do not have pathogenic mutations of epigenetic modifiers, such as EZH2, MLL2/KMT2D, MLL3/KMT2C, EP300 and ARID1A, which have been reported in FLs in the literature, whereas Bcl-2(+)/IGH-BCL2(+) tFLs are probably pathogenic/pathogenic missense mutations or frameshift mutations of these genes. Additionally, novel mutations in TET2 and EP400 were detected in Bcl-2(-)/IGH-BCL2(-) tFLs. Conclusions Different genetic and epigenetic abnormalities might be involved in the oncogenesis of Bcl-2(-)/IGH-BCL2(-) tFLs from Bcl-2(+)/IGH-BCL2(+) tFLs and other FLs.