NCMM Tuesday Seminar: Martin Burkert

Martin Burkert: Mapping the cell-of-origin of malignant cells

Abstract: Somatic genomes accumulate dozens of mutations every year and the resulting somatic mutation landscape is strongly shaped by chromatin organisation. Recent studies suggest that the locus of somatic mutations represents a memory of the cell's epigenetic state and that it can be utilized to study the cell-of-origin (COO) of tumors. Here, we developed a novel computational method to infer the ancestral epigenome from regional patterns of somatic mutagenesis. We validated our approach using genomes from 30 normal cell types and applied it to study the COO of 25 pediatric and adult cancer types. Our results demonstrate for blood genomes that somatic mutations derived from hematopoietic progenitor cells occur most likely in hematopoietic stem cells. In contrast, we inferred across 127 tissue types and 31 blood cell types memory B cells as the ancestral epigenome and COO of chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma. Moreover, our results suggest granulocyte-monocyte and monocyte-dendritic cell progenitors as the COO of acute myeloid leukemia. Our method allows us to assess the ancestral epigenome and COO solely from whole genome sequencing and thus provides a novel approach to characterize cellular states underlying malignant transformation.