Mutational landscape of gray zone lymphoma

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• The mutational landscape of gray zone lymphoma (GZL) and its relationship to similar lymphomas remain poorly understood.
• Epstein-Barr virus (EBV) status and anatomical presentation may influence lymphoma characteristics.

Purpose of the Study:

• To establish the mutational landscape of EBV-negative GZL.
• To compare GZL mutational profiles with EBV-positive diffuse large B-cell lymphoma (DLBCL) and other related lymphomas like classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBCL).

Main Methods:

• Whole-exome sequencing was performed on a discovery cohort of GZL and polymorphic EBV+ DLBCL (poly-EBV-L) cases.
• Targeted sequencing of 217 genes was used for an extension cohort of GZL and poly-EBV-L.
• Mutational profiles were analyzed in relation to thymic niche involvement and compared with cHL, PMBCL, and DLBCL.

Main Results:

• GZL with thymic niche involvement showed mutation profiles similar to cHL and PMBCL, with recurrent mutations in SOCS1, B2M, and TNFAIP3.
• GZL without thymic niche involvement exhibited distinct mutations related to apoptosis defects (TP53, BCL2) and fewer mutations in NF-κB signaling pathways.
• Poly-EBV-L cases had a unique mutational profile including STAT3 mutations and a lower mutation load compared to EBV-negative GZL.

Conclusions:

• GZL presents distinct mutational patterns based on thymic niche involvement.
• Thymic GZL shares a common cell of origin and evolutionary path with cHL and PMBCL.
• Non-thymic GZL has a unique molecular signature characterized by apoptosis-related gene mutations.