Molecular Mechanisms in the Pathogenesis of Composite Lymphomas

Introduction If two distinct lymphomas occur concurrently in a patient this is named composite lymphoma. Such lymphomas often involve a classical Hodgkin lymphoma (HL) and a B cell-Non-Hodgkin lymphoma (B-NHL). In most instances such composite lymphomas are clonally related and originate from a common germinal center B cell, which can be detected by identical rearranged immunoglobulin variable region genes. Several studies analysing selected candidate genes have identified shared as well as distinct transforming events in single genes of clonally related composite lymphomas, indicating that the malignant cells developed separately from a common precursor cell. Thus, composite lymphomas are elegant models to study the multi-step transformation process in lymphomagenesis. Moreover, there is indication that even composite or consecutive B- and T-cell lymphomas may share transforming events, as somatic genetic lesions can be already detected in hematopoietic precursor cells of lymphoma patients and elderly healthy individuals.

Methods We isolated lymphoma and non-tumor cells by microdissection from several composite lymphomas involving HL and B-NHL as well as by flow-cytometric cell sorting for two B- and T-cell-NHL combinations. For the composite HL and B-NHL their rearranged immunoglobulin were amplified. For all samples, whole exome sequencing was performed.

Results We analyzed composite lymphomas of HL combined with mantle cell lymphoma, splenic marginal zone lymphoma or follicular lymphoma, and two B- and T-cell-NHL combinations which included a plasma cell leukemia co-occurring with an anaplastic large cell lymphoma and a chronic lymphatic leukemia combined with a T-cell prolymphocytic leukemia. Analysis of the immunoglobulin variable region genes of combined HL and B-NHL showed that most HL were clonally related to the combined B-NHL. Whole exome sequencing of the two lymphoma components and of non-tumor cells revealed that in each of the cases shared somatic mutations were present. All cases also carried a substantial number of non-shared somatic mutations.

Conclusion Our preliminary evaluation of the whole exome sequencing data indicates that in all cases analyzed by us, numerous shared as well as distinct non-synonymous mutations are found. This supports the close relationship of HL to B-NHL, and eluminates ways how from a common pre-malignant precursor, two distinct lymphoid malignancies can develop.

• References

• 1 Schmitz R, Renné C, Rosenquist R, Tinguely M, Distler V, Menestrina F, Lestani M, Stankovic T, Austen B, Bräuninger A, Hansmann M-L, Küppers R. ( 2005; ) Insight into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin and non-Hodgkin lymphomas. Leukemia, 19 , 1452-1458
• 2 Küppers R, Dührsen U, Hansmann M-L. ( 2015; ) Pathogenesis, diagnosis and treatment of composite lymphoma. Lancet Oncol, 14 , e435-e446