Genomic Landscape of Metastatic Prostate Cancer Unveiled in New Study

Analysis of Prostate Tumors Reveals Clues to Cancer’s Aggressiveness
Sequencing finds genetic errors common in metastatic tumors

PSA Rising August 4 2018. 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.

Using genetic sequencing, scientists revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The multicenter study lays the foundation for finding new ways to treat prostate cancer, particularly for the most aggressive forms of the disease.

Genomic hallmarks of metastatic prostate cancer
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Graphical Abstract, source: Cell

The study  examined the genomes of tumors that grew and spread quickly. A common treatment for prostate cancer, beyond the traditional options of surgery, chemotherapy and radiation, involves androgen deprivation therapy, in which drugs are used to block testosterone from binding to the androgen receptor. Since prostate tumors are often hormone-driven cancers, blocking testosterone from binding this receptor slows tumor growth.

All the men in this study had tumors that developed resistance to androgen deprivation therapy, meaning the androgen receptor is always switched on, fueling the tumor, whether testosterone is present or not. Patients in this situation have no effective treatment options. The researchers showed that more than 80 percent of these patients had mutations that help explain the aggressiveness of their cancers; these genetic errors activated the androgen receptor.

As reported in the July 19, 2018 issue of Cell, a team led by investigators at UC San Francisco,  Washington University in St. Louis,  and  University of Michigan 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, these structural changes 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.

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 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 using this technique to map the genomes of biopsy samples from 300 men with metastatic refractory prostate cancer, building what Feng said is “one of the world’s best biorepositories” for the study of the disease.

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 study could aid the search for better therapies to treat aggressive prostate cancer,” said co-first author Christopher A. Maher, PhD, an associate professor of medicine and an assistant director at The McDonnell Genome Institute at Washington University School of Medicine. “More immediately, the new information could help doctors find ways to identify which patients may develop aggressive tumors, and help guide their treatment decisions.”

Feng said that the new work should build on a recent trend toward more personalized therapies for prostate cancer. 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, said Feng, who believes the data from the new study offer new leads for the treatment of metastatic disease.

“The impact of the observations from this project reflect a remarkable collaborative effort,” said Dr. Small. “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 researchers also found important roles for other genes known to be involved in cancer, including those that help with DNA repair, such as TP53 and BRCA2.

More than 160,000 cases of prostate cancer are diagnosed each year in the U.S. While some 80 percent of prostate cancer patients have tumors that are slow-growing and have effective treatment options, about 20 percent of such patients develop the most aggressive forms of the disease — the focus of the new study.

Link & Sources

Original research article  Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. July 19, 2018.

The multicenter study was led by led by first authors David Quigley, PhD, of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC),  Ha X. Dang, PhD, a senior scientist at Washington University, and Shuang G. Zhao, MD, of the University of Michigan.

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.

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.

Study funding: 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. Additional money was provided by Goldberg-Benioff Research Fund for Prostate Cancer Translational Biology; the V Foundation for Cancer Research; the BRCA Foundation; the Department of Defense (DOD); the Early Detection Research Network of the National Cancer Institute; the National Institutes of Health, and other grants and awards.
Sources: News releases 19-Jul-2018 12:05 AM EDT by Pete Farley UCSF News Center and by Newsroom at Washington University in St. Louis.
Compiled and edited August-4-2018 for PSA Rising by J. Strax.