Different primary thyroid B-cell lymphomas show overlapping mutation profile, suggesting involvement of a common pathogenic process

Primary thyroid lymphomas commonly originate from a background of Hashimoto’s thyroiditis and comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Thyroid EMZL harbours a distinct mutation profile, but whether this discriminates them from thyroid FL and DLBCL is unknown. To investigate this, we have investigated 42 EMZL (11 BCL6-tr+ve), 21 FL (5 BCL2-tr+ve, 10 BCL6-tr+ve, 1 both BCL2/BCL6-tr+ve) and 34 DLBCL of the thyroid. Targeted NGS revealed a remarkable overlap in the mutation profile among thyroid EMZL, BCL2-tr-ve FL and DLBCL, all showing frequent mutations in TET2, IGLL5, TNFRSF14, CD274, GNA13, FAS, KLF2 and TNFAIP3. In contrast, BCL2-tr+ve FL of the thyroid showed frequent BCL2, KMT2D, CREBBP, EZH2, but not TET2 and CD274 mutations. Genomic analysis of BCL6 translocation by targeted locus capture NGS showed different genomic configurations between thyroid FL and EMZL. In thyroid FL, majority of BCL6 translocations placed its coding exons under the transcriptional control of the IGH switch region super-enhancer or its partner genes, potentially resulting in BCL6 constitutive expression. In contrast, majority of BCL6 translocations in thyroid EMZL juxtaposed the BCL6 gene to the IGHJ/D region without encompassing the E enhancer or its partner genes in an opposite orientation, thus less likely to lead to constitutive BCL6 transactivation. The above genetic changes likely dysregulate B-cell maturation and peripheral tolerance, thus offer significant molecular insights into the pathogenesis of thyroid lymphomas, particularly underpinning autoimmunity in the lymphomagenesis and potentially explaining the overlap in histopathology between EMZL and FL.