Biology and Microenvironment
Anna Lollies, Markus Schneider, Sylvia Hartmann, Stephan Mathas, Enrico Tiacci, Marc Andree Weniger, Patricia Johansson, Jan Dürig, Ludger Klein-Hitpass, Martin-Leo Hansmann and Ralf Küppers
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany, Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt am Main, Germany, Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany, Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, Italy, Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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 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. Recently, 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. In the transformation process, distinct genetic lesions happened in the daughter cells of the common malignant precursor and lead to the development of two distinct lymphomas from one cell of origin. Thus, composite lymphomas are very elegant and unique 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.
Here, we performed whole exome sequencing of isolated lymphoma cells from several composite lymphomas involving clonally related HL and B-NHL as well as B- and T-cell-NHL combinations with the aim to identify shared as well as distinct genetic lesions in composite lymphomas. We analyzed composite lymphomas of HL combined with mantle cell lymphoma, splenic marginal zone lymphoma or chronic lymphatic leukemia 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 B cell composite lymphomas showed that most cases were clonally related. The exome sequencing analysis will allow us to further explore the oncogenic mechanisms in the pathogenesis of composite lymphomas. 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.