A comprehensive genetic analysis of metastatic prostate cancer has, for the first time, revealed a number of major ways in which abnormal alterations of the genome propel this aggressive form of the disease.
As reported in the July 19, 2018 issue of Cell, a team led by investigators at UC San Francisco has discovered widespread structural changes in prostate cancer genomes that take the form of abnormal duplications, insertions, or deletions of genetic sequences. These structural changes are associated with the loss of function of genes that normally maintain the genome’s integrity by repairing damaged DNA, and they also result in the activation of cancer-driving oncogenes and inactivation of genes that suppress tumor growth. In more than 80 percent of the patients studied, they also create numerous extra copies of “enhancer” sequences that promote the expression of a key oncogene known as the androgen receptor.
This last finding is particularly notable, because the androgen receptor, which is activated by testosterone and other male sex hormones, is the primary target of most medications used as second-line treatments when prostate cancer recurs after surgery and radiation therapy. Because extra copies of androgen-receptor enhancer sequences would presumably amplify the activity of these receptors, this structural change may help explain the stubborn resistance to androgen-blocking treatments that often emerges in metastatic disease.
“This study has provided a tremendous resource that will be publicly available to the prostate cancer research community,” said physician-scientist Felix Y. Feng, MD, associate professor of radiation oncology at UCSF and co-senior author of the new study. “The data should now generate a very large number of scientific hypotheses that will collectively improve our understanding of what drives metastatic prostate cancer, and down the road, which genomic alterations can be used to guide personalized therapies.”