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Common Genetic Errors In Metastatic Tumors

Chicago(July 21, 2018): Using genetic sequencing, a study led by Washington University School of Medicine in St. Louis and the University of California, San Francisco has revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. 

The researchers analyzed the whole genomes, all of the DNA, including all of each tumor’s genes of metastatic prostate tumors, and found that many of these tumors have problems in the sections of the genome that tell protein-coding genes what to do.

The researchers found that about 80 percent of the aggressive tumors studied had the same genetic alterations in a region of the genome that controls the androgen receptor. This genetic error dialed up levels of androgen receptor on prostate cancer cells. Such receptors bind to male hormones such as testosterone and drive tumor growth. “This was one of the most surprising findings,” said co-first author Christopher A. Maher, an associate professor of medicine and an assistant director at the McDonnell Genome Institute at Washington University School of Medicine. “We saw too many repeated copies of DNA in this region of the genome. In some of these patients, the androgen receptor looks totally normal. But they have too much androgen receptor because the receptor’s regulatory region is dialed up, which would be missed by the protein-coding focused sequencing studies.”

All the men in this study had tumors that developed resistance to androgen deprivation therapy, which means 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.

The researchers also found important roles for other genes known to be involved in cancer, including those that help with DNA repairs, such as TP53 and BRCA2.

More than 160,000 cases of prostate cancer are diagnosed each year in the United States. 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 study, which has laid the foundation for finding new ways to treat prostate cancer, particularly for the most aggressive forms of the disease, was published July 19 in the journal Cell.

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