engleski

The Mutational Landscapes of Cancers Serve as Records of Early Malignant Transformation

A fundamental question in cancer biology is how the cell lineage influences the cell’s susceptibility to malignant transformation. Cell properties are encoded in the cell type-specifi c chromatin structure and we previously demonstrated that the landscape of somatic mutations in cancer is associated with the chromatin marks of the cell-of-origin (Polak et al, Nature, 2015). Many of these mutations accumulate before malignant transformation and serve as a historical record of the original normal cell. Here, we show that this principle is generalizable to common cancer types and provides new insights into the molecular events of cancer initiation. We extended our analysis to include 2, 641 whole genomes across 30 cancer types and epigenetic modifi cations from 98 normal tissue types. We found that 28/30 cancer types originated from a biologically plausible cell-of-origin. In 25 cancer types, the tumor originated from a cell type that was its direct normal cell counterpart (or a related cell type). In three cancer types (esophageal, pancreatic ductal and biliary adenocarcinomas) the best-matched normal cell type indicated metaplasia. In the remaining two cancer types, we did not fi nd a good match among the normal cell types, due to the lack of relevant epigenetic data. We analyzed in more detail different breast cancer subtypes. We found that basal-like tumors appear to originate from luminal progenitor cells, while all other subtypes (luminal A, luminal B, and HER2-enriched) arise from mature luminal cells. Furthermore, this association held true when accounting for various gene inactivation events. Irrespective of the exact mechanism of inactivation, all BRCA1/2- and RAD51C-altered basal-like tumors best matched to luminal progenitors while BRCA1/2- and CHEK2 -mutated luminal A/B subtypes best matched mature luminal cells, implying that the inactivation of specific genes was less crucial than the cell-of- origin for driving the formation of subtypes. Taken together, our findings highlight the crucial role of the specific cell type of origin in shaping the mutational landscape and early tumor evolution.

Cancer genomics ; Cell-of-origin

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