Two new studies — one from a group led by an NIEHS-funded researcher and the other co-authored by an in-house NIEHS scientist — may lead to improved prediction of prostate cancer.
The two groups used different methods, but taken together, the results suggest that analyzing epigenetics, or the changes to DNA that do not change the genetic code itself, could predict both the development of the disease and the likelihood of recurrence.
Endocrine disruptors, stem cells, and prostate cancer
The study by Shuk-Mei Ho, Ph.D., and colleagues at the University of Cincinnati College of Medicine was published in the journal Epigenetics. The scientists exposed newborn rats to small, short doses of two endocrine disrupting chemicals, bisphenol A and estradiol benzoate, a synthetic form of estrogen.
The rats exhibited epigenetic changes in prostate stem cells that appeared to make the animals more vulnerable to development of prostate cancer. Sophisticated genomic analyses pointed to a set of seven genes that appear to influence prostate stem cells. Epigenetic reprogramming of these genes, in the form of changes to DNA methylation, made them more susceptible to carcinogenic exposures later in life.
Matching the seven rat genes with their human counterparts in The Cancer Genome Atlas proved fruitful. “We found that these seven genes also were associated with recurrence-free survival of prostate cancer patients,” said Ho, “giving human relevance to these results.”
The seven genes could have clinical value as a predictive biomarker for the recurrence of prostate cancer or they could predict how aggressive the disease will be. Currently, even an invasive biopsy cannot accurately forecast these aspects of the cancer.
“Being able to differentiate which cancer will develop aggressively [from the others] would be very helpful for many men, especially men over seventy years old, who are diagnosed with prostate cancer,” Ho observed.
NIEHS health scientist administrator Thad Schug, Ph.D., cautioned that the group’s work is still in its early stages. “While these findings are still preliminary, they certainly hold promise for development of robust epigenetic biomarkers for classifying prostate cancers,” he said.
Profiling tumor DNA leads to new prediction method
Tenure-track NIEHS scientist Shanshan Zhao, Ph.D.(https://www.niehs.nih.gov/research/atniehs/labs/bb/staff/zhao/index.cfm), continues to collaborate with her former colleagues at Fred Hutchinson Cancer Research Center in Seattle, where a large group, or cohort, of prostate cancer patients has been closely followed for more than 20 years.
Her team profiled DNA methylation in primary tumors in the group and in an independent cohort from the East Virginia Medical School. The results, published in the journal Clinical Cancer Research, involved a panel of eight novel, validated biomarkers that can distinguish patients with metastatic, lethal prostate cancer from men whose disease did not recur five years after prostate surgery (see summary(https://stage.niehs.nih.gov/news/newsletter/2016/9/papers/dir/index.htm#a2)).
The current clinical prediction standard, the Gleason score, also called the Gleason sum, is derived from analyzing tissue obtained from a biopsy of a prostate tumor. The researchers are working to improve classification of tumors as passive or aggressive by combining the panel of eight epigenetic biomarkers with the Gleason sum.
“We are hoping to further validate these identified epigenetic biomarkers and develop a prostate cancer risk score based on these biomarkers and some other clinical features, such as Gleason sum,” said Zhao. “Hopefully, clinicians can use these scores to inform patients about their risks and help them make treatment decisions.”
“This paper is a good example of team science and how biostatisticians can impact public health and clinical practice,” noted Shyamal Peddada, Ph.D.(https://www.niehs.nih.gov/research/atniehs/labs/bb/staff/peddada/index.cfm), acting head of the NIEHS Biostatistics and Computational Biology Branch.
Cheong A, Zhang X, Cheung YY, Tang WY, Chen J, Ye SH, Medvedovic M, Leung YK, Prins GS, Ho SM. 2016. DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk. Epigenetics. doi:10.1080/15592294.2016.1208891 [Online 14 Jul 2016].
Zhao S, Geybels MS, Leonardson A, Rubicz R, Kolb S, Yan Q, Klotzle B, Bibikova M, Hurtado-Coll A, Troyer D, Lance R, Lin D, Wright JL, Ostrander EA, Fan JB, Feng Z, Stanford JL. 2016. Epigenome-wide tumor DNA methylation profiling identifies novel prognostic biomarkers of metastatic-lethal progression in men with clinically localized prostate cancer. Clin Cancer Res. doi:clincanres.0549.2016 [Online 29 Jun 2016].