Common origin and somatic mutation patterns of composite lymphomas and leukemias

When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES). Analysis of their IGV genes revealed that three composite B-cell lymphomas originated from common germinal center-experienced B cells. WES identified shared somatic mutations in the lymphomas of these clonally related composite lymphomas, indicating their derivation from a common, pre-malignant precursor. Most mutations were restricted to one or the other of these lymphomas, likely explaining how distinct lymphomas developed from a common ancestral B cell. In the two B-cell/T-cell lymphoma cases, and a composite clonally unrelated HL/chronic lymphocytic leukemia, the lymphoma partners did not share any somatic mutations. In three cases, we identified potentially oncogenic variants also in cells serving as constitutional controls. These variants may have contributed to development of a composite lymphoma/leukemia. We provide additional evidence of frequent clonal relation in composite lymphomas, highlight the multistep transformation process of related lymphomas with a likely pre-malignant intermediate common precursor, and support the importance of constitutional variants in lymphomagenesis.