Large-scale epigenomic reprogramming links anabolic glucose metabolism to distant metastasis during the evolution of pancreatic cancer progression

Abstract

The present invention relates to a method of identifying epigenetic reprogramming. Identifying epigenetic reprogramming comprises detecting large organized heterochromatin lysine (K)-9 modified domains (LOCKs) and large DNA hypomethylated blocks in a sample containing DNA from a subject having cancer, for example, PDAC.

1 - 12 . (canceled) 
     
     
         13 . A method for identifying a subject's responsiveness to a treatment regime comprising analysis of changes in global chromatin modifications in a DNA sample from the subject prior to and following the treatment regime to provide a prognosis or analysis of responsiveness to the treatment regime. 
     
     
         14 . A The method of  claim 13 , wherein identifying changes in global chromatin modification comprises identifying changes in large-organized heterochromatin lysine (K)-9 modified domains (LOCKs), changes in large LOCKs, and/or changes in euchromatin domains (ECDs). 
     
     
         15 . The method of  claim 14 , wherein analyzing is by combinatorial methods. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15 , wherein combinatorial methods comprise Western blotting, immunohistochemistry, chromatin immunoprecipitation (ChIP), whole genome bisulfite sequencing, or a combination thereof. 
     
     
         18 . The method of  claim 13 , wherein the sample is DNA from a cancer cell from a solid tumor. 
     
     
         19 . The method of claim  1 , wherein the solid tumor is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         20 . The method of  claim 14 , wherein identifying changes in LOCKs comprises identifying changes in H3K9Me2 and/or H4K9Me3. 
     
     
         21 . The method of  claim 20 , wherein detecting a loss of H3K9Me2 in LOCKs in a cell from a primary tumor or from a local metastasis is indicative of a likelihood of evolution to distant metastasis. 
     
     
         22 . The method of  claim 14 , wherein identifying changes in ECDs comprises identifying changes in H3K26Me3 and/or H3K27Ac. 
     
     
         23 . The method of  claim 22 , wherein detecting local reprogramming of H3K26Me3 and/or H3K27Ac over differentially expressed genes withing ECDs in a cell from a primary tumor or from a local metastasis is indicative of a likelihood of evolution to distant metastasis. 
     
     
         24 . The method of  claim 14 , wherein a LOCK has a length ranging from about 100 kb to 30 Mb. 
     
     
         25 . The method of  claim 14 , wherein a LOCK has an average length of about 232 Kb-311 Kb. 
     
     
         26 . The method of  claim 14 , wherein a large LOCK has a length ranging from about 500 Kb to 30 Mb. 
     
     
         27 . The method of  claim 14 , wherein a large LOCK has an average length of about 73 0 Kb-1,340 Kb. 
     
     
         28 . The method of  claim 14 , wherein an ECD has a length ranging from about 50 kb to 12 Mb. 
     
     
         29 . The method of  claim 14 , wherein a LOCK has an average length of about 207 Kb-277 Kb.