ISEMPH Presentation: Jeffrey Townsend

ISEMPH - Jeffrey Townsend, Yale University

"Metastatic lineages can arise early and exhibit multiple genetic origins within primary tumors"
Jeffrey Townsend
Department of Biostatistics
Yale University 
It has long been understood that tumorigenesis is an evolutionary process associated with the accumulation of somatic mutations. However, many aspects of that process that are fundamental to cancer biology and targeted treatment have been challenging to reveal. To discover the timing of genetic divergence and the evolutionary relation of metastatic lineages to primary tumors, we sequenced normal, primary and 139 metastatic cancers from 40 subjects with 13 different cancers. To infer the evolutionary relationships among these tumor samples within each subject, we applied phylogenetic inference to the aligned concatenated somatic sequence variants. We found that metastatic tumor lineages can arise early in the molecular evolution of cancers. Furthermore, we found that metastatic tumors can arise from different lineages within primary tumors, rather than always from a single metastasis-adapted descendant lineage. By estimating sequences at ancestral nodes of the cancer evolutionary tree and inferring on which branch each mutation occurred, we linked driver mutations to the early phases of tumorigenesis and metastasis. These findings provide critical insight into the dynamic origins of metastases and the temporal order of major cancer driver mutations, information that can play a key role in determining whether pharmaceutical interventions can successfully target all cancerous tissues.