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Projects

Pfeifer Laboratory

DNA methylation and cancer

One of the lab’s primary projects is studying the mechanisms and biological significance of CpG island hypermethylation in cancer by investigating the molecular pathways that lead to DNA methylation changes in tumors. The lab’s hypothesis is that specific factors such as carcinogenic agents, oncogene activation, inflammation, mechanisms related to the Polycomb repression complex, and imbalances between methylation and demethylation pathways drive the common event of CpG island methylation in tumors.

The role of 5-methylcytosine oxidation in development and disease

The Pfeifer Lab has previously found that 5hmC is extremely rare in human cancer; therefore, this knowledge could lead to new biomarkers for malignant cancer. The lab hypothesizes that defects in 5-methylcytosine (5mC) oxidation are responsible for different DNA methylation patterns in tumors and, potentially, other diseases. To test this hypothesis, the Pfeifer Lab has established and used methodology for genome-wide mapping and precise quantification of 5mC and 5hmC, with the goal of determining genomic distribution of 5hmC in normal tissues, in malignant tumors and in disease states. To this end, the lab focuses on solid tumors and investigates the role of the TET proteins that catalyze the conversion of 5mC to 5hmC and additional oxidized bases. The lab conducts basic mechanistic studies of TET and TET-associated proteins, along with their regulation, abnormalities in cancer and their roles in cell differentiation and CpG island integrity.

Origins of Mutations in Cancer

Cancer genomes are characterized by large numbers of mutations with different mutational signatures found in different tumor types. With the exception of sunlight-induced skin cancers and smoking-associated lung cancers, there are only a few other cases where the mechanisms of the mutations’ origin are understood. The lab focuses on a few such cancer types that include liver cancer and esophageal cancer, for which a mechanism based on the mutation data can be proposed. Towards analyzing novel mechanisms of mutagenesis, the Pfeifer Lab has developed new, highly sensitive methodology to characterize specific DNA damage at every position in the human genome.