Common origin and somatic mutation patterns of composite lymphomas and leukemias

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Composite lymphomas present a diagnostic challenge, raising questions about their cellular origins—whether a single precursor or independent development.
• Understanding the clonal relationship in these lymphomas is crucial for accurate diagnosis and treatment strategies.

Purpose of the Study:

• To investigate the clonal origins of composite lymphomas using whole exome sequencing (WES).
• To determine if concurrent or sequential lymphomas in a patient originate from the same or different precursor cells.

Main Methods:

• Whole exome sequencing (WES) was performed on four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas.
• Analysis included IGV gene sequencing and identification of shared and distinct somatic mutations.
• Constitutional control cells were analyzed for potentially oncogenic variants.

Main Results:

• Three of the studied composite B-cell lymphomas originated from common germinal center-experienced B cells, confirmed by shared somatic mutations.
• Distinct mutations within these clonally related lymphomas explained their varied phenotypes.
• Two B-cell/T-cell lymphoma cases and one HL/chronic lymphocytic leukemia case showed no shared mutations, indicating independent origins.
• Potentially oncogenic constitutional variants were identified in three cases, possibly contributing to lymphomagenesis.

Conclusions:

• Composite lymphomas frequently exhibit clonal relationships, originating from a common, pre-malignant B-cell precursor.
• Multistep transformation processes, involving a common ancestral cell and accumulating distinct mutations, lead to diverse lymphoma types.
• Constitutional genetic variants play a significant role in the development of composite lymphomas and leukemias.