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 prostate cancer oncogene known as the androgen receptor gene.
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.”
The prognosis for primary, localized prostate cancer varies depending on risk factors, such as a patient’s level of prostate-specific antigen, or PSA, and many cases are effectively treated with a combination of surgery and radiation therapy.
In some cases, however, cancer will persist or recur. Male sex hormones are known to drive prostate tumor growth, and in these patients, and in patients whose cancer has already metastasized, therapy known as androgen deprivation therapy—the therapeutic withdrawal of male sex hormones—is highly effective. But most patients eventually develop resistance to this therapy and the cancer recurs, resulting in the “metastatic castration-resistant” form of the disease that was the subject of the new study.
Previous genomic studies of prostate cancer have focused on the primary, localized form of the disease, or have only examined the “exome,” the 1.5 percent of the genome that includes genes, which in turn contain instructions for the manufacture of proteins. By contrast, the new study—led by first authors David Quigley, PhD, of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC), Ha X. Dang, PhD, of Washington University in St. Louis, and Shuang G. Zhao, MD, of the University of Michigan—employed a whole-genome approach, which deciphers the sequences of important regulatory regions in the massive swath of the genome that lies outside genes.
Beginning about five years ago, the research team began collecting biopsy samples from men with metastatic refractory prostate cancer. They now have about 300 such samples, “one of the world’s best biorepositories” for the study of the disease, said Feng. The project was made possible by a $10 million grant awarded in 2012 by three philanthropic organizations—Stand Up To Cancer, the Prostate Cancer Foundation, and the Movember Foundation—to a West Coast–based “Dream Team” of researchers led by UCSF’s Eric J. Small, MD, co-senior author and chief scientific officer at HDFCCC, and co-led by Owen N. Witte, MD, co-author and University Professor at UCLA’s Molecular Biology Institute.
Joining Feng and Small as co-senior authors were Christopher Maher, PhD, of Washington University in St. Louis, and Arul M. Chinnaiyan, MD, PhD, of the University of Michigan.
In addition to many-fold abnormal copies of the androgen-receptor enhancer, the new research, in which biopsy samples from more than 100 men were analyzed, reports structural genomic alterations that activate well-known cancer-driving genes such as MYC, and conversely, alterations that would reduce the activity of “tumor suppressor” genes such as TP53 and CDK12. Genes involved in DNA repair, such as BRCA1 and BRCA2, previously implicated in whole-exome studies of prostate cancer, were also found to be damaged by structural changes.
“This landmark study by the West Coast Dream Team reveals that metastatic castration-resistant prostate cancer is driven by vast genomic structural variations, and provides new insights into the mechanisms of disease progression and treatment resistance,” said Howard Soule, PhD, executive vice president and chief science officer of the Prostate Cancer Foundation. “This wealth of data will enable many new discoveries and change the way we think about prostate cancer biology and treatment.”
Feng said that the new work should build on a recent trend toward more personalized therapies for metastatic prostate cancer. He said that recent studies suggest, for example, that prostate cancer characterized by CDK12 mutations may respond to the form of immunotherapy known as checkpoint inhibitors, and that another class of drugs called PARP inhibitors may help prostate cancer patients in whom the BRCA DNA-repair genes are affected.
“The impact of the observations from this project reflect a remarkable collaborative effort across the multiple institutions of the West Coast Prostate Cancer Dream Team, and beyond,” said Small, also professor of medicine and of urology at UCSF, and chief of the Department of Medicine’s Division of Hematology and Oncology. “These whole-genome sequencing data are particularly impactful in that they are derived from biopsies of metastases in men with castration-resistant prostate cancer, for whom careful, longitudinal, clinical annotation exists.”
The UCSF, UCLA, Washington University, and University of Michigan researchers were joined by scientists from Illumina, Inc.; Oregon Health and Science University; the University of British Columbia; the University of Minnesota; UC Davis; UC Santa Cruz; Thomas Jefferson University; the University of Toronto; Duke University; and the University of Minnesota. A complete list of authors is available in the published study.
In addition to Stand Up to Cancer, the Prostate Cancer Foundation, and the Movember Foundation, the work was supported by the Goldberg-Benioff Research Fund for Prostate Cancer Translational Biology; the V Foundation for Cancer Research; the BRCA Foundation; the Department of Defense; the Early Detection Research Network of the National Cancer Institute; and the National Institutes of Health.
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