The Genomic Evolution of Prostate Cancer
Technical Report,30 Sep 2014,29 Sep 2015
University of Chicago Chicago United States
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Prostate cancer is a heterogeneous disease characterized by diverse outcomes. A subset of patients originally diagnosed with low risk disease go on to be diagnosed with high grade disease. It is important to determine to what extent this is due to undersampling on the initial biopsy, and to what extent low grade disease evolves. In addition, multiple genetic alterations are associated with disease evolution in response to therapy. This project aims to characterize evolution of prostate cancer. Completed work used exome sequencing to evaluate the relationship of low grade foci, high grade foci, and metastases in radical prostatectomy specimens. This work demonstrates that coincident low and high grade disease are distantly related, indicating that an early parental clone can give rise to both low grade and high grade disease. Conversely, lymph node metastases are closely related to high grade cancer. Alterations in the TP53 pathway are associated with high grade disease and lymph node metastases. The observation that alterations identified in lymph node metastases can also be found at low levels in high grade intraprostatic foci led to additional evaluation of high grade index foci, demonstrating considerable heterogeneity across the focus and evidence of commingled subclones. Aims still under investigation are evaluating the relationship between coincident conventional prostate cancer and the aggressive variant ductal adenocarcinoma, and using circulating tumor cells to evaluate the evolution of castrate resistant metastatic cancer from primary foci.