Dataset Information


Large-scale epigenetic reprogramming is punctuated late during the evolution of pancreatic cancer progression [BS-Seq]

ABSTRACT: During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. BS-Seq of 4 patients (A13, A38, A124 and A125). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets). Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates. Patient A124 included 2 primary tumors and 1 normal pancreas.

ORGANISM(S): Homo sapiens  

SUBMITTER: Xin Li   Oliver G McDonald  Christine Iacobuzio-Donahue  Andrew P Feinberg 

PROVIDER: E-GEOD-63123 | ArrayExpress | 2016-10-24



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