engleski

The mutation landscape of cancers serves as a record of early malignant transformation

How the cell lineage influences a tissue's susceptibility to malignant transformation is a fundamental question in cancer biology, which has been barely addressed in cancer genomics thus far. Cell properties are encoded in the cell type- specific chromatin structure and we previously demonstrated that the cell-of-origin (COO) chromatin organization is a key determinant of the landscape of somatic mutations, which accumulated over lifetime serving as a memory of the historical cell lineage (Polak et al, Nature , 2015). We now show that this principle is generalizable to common tumor types and offers insights into the molecular events of cancer initiation. We extended our work to 2, 641 genomes from 30 cancer types and epigenetic modifications from 98 normal tissues. In 25 cancer types, the tumor originated from a cell type that was its direct cellular counterpart or a close proxy ; in only two, there was no match or a close proxy ; and in the remaining three (esophageal, pancreatic ductal and biliary adenocarcinoma) the best matched cell type suggested metaplasia to stomack mucosa like tissue.The cellular context of breast tumor formation was investigated in more detail, showing that the COO, and not the gene inactivation event, determines the subtype. Basal- like tumors appeared to arise from luminal progenitor cells, while all other subtypes arose from mature luminal cells. Furthermore, irrespective of the inactivation mechanism (pathogenic germline, somatic truncating or epigenetic silencing event), 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. Finally, we observed that tumor type-specific driver genes reside in genomic regions that are defined by a highly active chromatin environment in their COOs. This highlights their essential role in cell type differentiation and implies the acquisition of somatic mutations early, when the chromatin architecture still reflected the COO. Taken together, our findings shed light on the crucial role of the COO in shaping the mutational landscape and tumor evolution.

Cancer genomics ; Cell-of-origin

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