Largest-ever study of its kind led by the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center could improve treatment and change how risk of aggressive disease is determined.

By Wayne Lewis

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An international research team led by scientists in the Center for Genetic Epidemiology at the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center has singled out mutations in 11 genes that are associated with aggressive forms of prostate cancer. These findings come from the largest-scale prostate cancer study ever exploring the exome — that is, the key sections of the genetic code that contain the instructions to make proteins. The scientists analyzed samples from about 17,500 prostate cancer patients.

Today, oncologists customize care for certain individuals with aggressive prostate cancer with help from genetic tests. The results can inform treatment, as one class of targeted therapies has proved effective against some inherited prostate cancers. Test findings also can lead to genetic screening among patients’ family members, so they have the chance to take measures that reduce risk and to work with their doctors to be more vigilant in early detection.

The study, published in JAMA Oncology, uncovered mutations associated with higher risk for more-aggressive, deadlier prostate cancer that are not currently included on genetic test panels. The researchers also found some genes that are currently part of such panels are not linked with risk for aggressive disease.

“Very large studies are needed to inform the creation of gene panels used for testing,” said corresponding author Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and professor of Population and Public Health Sciences at the Keck School of Medicine. “Some of the genes in these panels were based on small studies and were not associated with prostate cancer in our study. We also found evidence that other genes perhaps ought to be added. The results aren’t completely definitive, but it’s clear that more work needs to be done to determine which genes oncologists should focus on in testing.”

Exploring prostate cancer genes in 17,500 patients

Combining information from 18 studies conducted in the U.S., Europe and Australia, the research team analyzed blood samples from prostate cancer patients of European descent, 9,185 of whom had aggressive disease and 8,361 who did not and compared the frequency of mutations among the two groups.

In the first stage of their investigations, Haiman and his colleagues sequenced the entire set of protein-coding genes among almost a third of participants. In the second stage, the researchers used samples from the remaining participants to zoom in on a subset of 1,749 genes that either had previously been associated with cancer or showed up as likely candidates in the first phase.

That subset included almost 200 genes involved with DNA repair. When that process is disrupted, it creates an opportunity for cancerous cells to arise and take hold.

An opportunity to advance treatment and prevention

The eleven genes that emerged as having mutations significantly linked to aggressive prostate cancer include BRCA2, also known for its connection to breast cancer. The list of genes, as well as those currently screened in genetic tests found not to be linked serious disease, could influence individualized treatment for prostate cancer, as well as screening.

Haiman notes that mutations found in the study also showed up in some patients who didn’t have aggressive disease.

“This suggests that mutations in these people may put them at greater risk for their cancer later becoming more advanced,’” he said. “While screening is focused on men with advanced disease or a family history, finding patients with less advanced disease who carry these genetic variants may enable them to receive targeted forms of treatment earlier on.”

The study does come with two important caveats. One is that, despite its large size, some mutations that drive risk for aggressive prostate cancer are so rare that even bigger studies are needed to clear up the picture. The other limitation is that the findings may differ outside of the population under investigation, people of European descent.

“It will be important for similar efforts to take place in men of African ancestry,” said Haiman, who is also co-leader of the Cancer Epidemiology Program at USC Norris cancer center. “That’s very important. These genes and perhaps others may be important, so additional work needs to be done in other populations.”

About this study

The first author of the study is Burcu Darst, PhD, an assistant professor at Fred Hutchinson Cancer Center and former postdoctoral research associate at the Keck School. Other co-authors from the Keck School are Xin Sheng, MS; Peggy Wan, MA; Loreall Pooler, BS; Lucy Xia, MS; and David Conti, PhD, a professor of Population and Public Health Sciences. The more than two dozen other co-authors of the study comprise researchers from the Institute of Cancer Research, London; the National Cancer Institute; the American Cancer Society; the University of Cambridge, the University of Oxford and the Royal Marsden NHS Foundation Trust, all in the UK; University of Texas MD Anderson Cancer Center; the Mayo Clinic; the Karolinska Institute in Sweden; the Cancer Council Victoria, Monash University and the University of Melbourne, all in Australia; Dana-Farber Cancer Institute; Aarhus University in Denmark; Northwestern University; and Johns Hopkins University.

This study was supported by the National Institutes of Health (R01CA196931, R00CA246063) and the Andy Hill CARE Foundation.