Timothy A. Chan, MD, PhD

The focus of the Chan laboratory is to understand the genomic basis of tumor development and progression. We utilize both large-scale genomic analyses and functional dissection to elucidate the drivers of oncogenesis.

Our research focuses on the following areas of investigation.

First, we are interested in identifying and characterizing novel, multisite tumor suppressor genes. We currently focus these efforts on glioblastoma (GBM), colon cancer, and breast cancer. We have developed large-scale genome-wide strategies that enable the efficient identification of genes that are mutated, deleted, or epigenetically silenced in cancer. We utilize these genome-wide genetic and epigenetic approaches to identify and characterize novel cancer genes that are important for the initiation and progression of cancer. Using these approaches, we have identified a collection of multisite tumor suppressors that may be fundamentally important for the development of many cancers.

For example, our lab has recently identified the E3 ligase PARK2 as a driver of loss in the frequently deleted region 6q25-27. We identified mutations of PARK2 in multiple human cancers and showed that these mutations disrupt the ability of PARK2 to regulate cyclin E and maintain genetic stability. Intriguingly, PARK2 mutations are also the most frequent cause of early onset Parkinson's disease. Our results indicate that mutation of PARK2 in the absence of an oncogenic context (i.e., in neurons) may lead to neurodegeneration but mutation of PARK2 in replication-competent cells may cooperate with other genetic lesions to initiate tumorigenesis.

Mutations of PARK2 in cancer and Parkinson’s disease

Current efforts focus on dissecting the molecular function of PARK2 in cancer using cell biological and animal models. Significant efforts are also under way to define the function of other tumor suppressors we have identified, including the PTPRD tyrosine phosphatase, and to identify other driver lesions in currently ill-defined regions of the cancer genome.

Second, our lab studies the molecular mechanisms underlying metastasis. It is increasingly clear that systematic epigenomic aberrations are fundamentally important for the development of metastatic lesions. We have recently shown, for the first time, that systematic derangement of the breast cancer methylome dictates the gene-expression changes underlying the metastasis transcriptome. Current efforts here focus on defining the metastasis epigenome and utilizing our findings to develop better prognostic and therapeutic options for patients.