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. 2021 Oct;79(4):521-532.
doi: 10.1111/his.14378. Epub 2021 Aug 3.

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

Yuichiro Hamamoto  1   2 , Yoji Kukita  3 , Masanori Kitamura  1 , Masako Kurashige  2 , Hiroaki Masaie  4 , Shigeo Fuji  4 , Jun Ishikawa  4 , Keiichiro Honma  1 , Tomoko Wakasa  5 , Hitoshi Hanamoto  6 , Mitsuyoshi Hirokawa  7 , Ayana Suzuki  7 , Eiichi Morii  2 , Shin-Ichi Nakatsuka  8
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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

Yuichiro Hamamoto et al. Histopathology. 2021 Oct.

Abstract

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.

Keywords: Bcl-2; epigenetics; follicular lymphoma; thyroid.

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