Abstract
Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference “cellular signals” in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of “fetalness” with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
Introduction
As cancer cells evolve from normal cells, they may retain patterns of messenger RNA (mRNA) characteristic of the cell of origin. In such cases, the cancer cell transcriptome may contain information that can identify the cancer cell of origin, its differentiation state, or trajectory towards a cancer cell. It is therefore conceivable that tumor transcriptomes can be used to identify the cells from which tumors arise and test fundamental hypotheses regarding tumor’s differentiation states, such as the “fetalness” of childhood tumors or the dedifferentiation of adult tumors towards a fetal state….
