Discovery may help distinguish indolent from lethal cancers
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"Cityscape" plot showing hypermethylation. Red Peaks indicate driver changes. Credit: Science/AAAS
In a genome-wide analysis of 13 metastatic prostate cancers, scientists at the Johns Hopkins Kimmel Cancer Center found consistent epigenetic ?signatures? across all metastatic tumors in each patient. The discovery of the stable, epigenetic ?marks? that sit on the nuclear DNA of cancer cells and alter gene expression, defies a prevailing belief that the marks vary so much within each individual?s widespread cancers that they have little or no value as targets for therapy or as biomarkers for treatment response and predicting disease severity.
A report of the discovery, published in the Jan. 23 issue of Science Translational Medicine, describes a genomic analysis of 13 men who died of metastatic prostate cancer and whose tissue samples were collected after a rapid autopsy.
Samples from three to six metastatic sites in each of the patients and one to three samples of their normal tissue were analyzed to determine the amount of molecular marks made up of methyl groups that attach to sites along the genome in a process known as DNA methylation. The process is part of an expanding target of scientific study called epigenetics, known to help drive cell processes by regulating when and how genes are activated. Mistakes in epigenetic processes also are known to trigger or fuel cancers.
?Knowing both the genetic and epigenetic changes that happen in lethal prostate cancers can eventually help us identify the most aggressive cancers earlier and develop new therapies that target those changes,? says Srinivasan Yegnasubramanian, M.D., Ph.D., assistant professor of oncology at The Johns Hopkins University School of Medicine. ?But there has been an open question of whether epigenetic changes are consistently maintained across all metastatic sites of an individual?s cancer.?
The research team found that while methylation patterns vary from one patient to another, many methylation patterns occur ?very consistently? within different metastatic sites in an individual patient.? They identified more than 1,000 regions of the genome where various types of DNA methylation were consistently maintained within their 13 subjects? genomes.
?As they evolve and grow, cancer cells acquire and maintain changes that enable them to continue thriving,? says Yegnasubramanian. ?We know that cancer cells maintain and pass along genetic changes in the nucleus of cells across metastatic sites, and our research now shows that epigenetic changes also are maintained to nearly the same degree.?
The scientists say that the consistent methylation changes they found appear to represent so-called driver changes critical to the cancer?s development and could be targets for treatment. By contrast, other methylation changes found only sporadically in the metastatic sites are more likely what are called passenger changes that occur by chance and are less promising as treatment targets or biomarkers than driver changes.
?Our study shows that for prostate cancer, at least, each person develops his own path to cancer and metastasis, and we can find a signature of that path in the epigenetic marks within their tumors,? says Yegnasubramanian, who envisions that certain epigenetic changes can be grouped into clusters to be used as biomarkers signaling a lethal cancer.
Yegnasubramanian and his team also plan to study how each of the driver changes work and how they influence cancer metastasis.
The research was funded by the Department of Defense Prostate Cancer Research Program (PC073533/W81XH-08-1-0049), the National Institutes of Health (CA58236, CA070196, CA113374, CA135008, GM083084), the Prostate Cancer Foundation Creativity and Challenge Awards, the Patrick C. Walsh Prostate Cancer Research Fund/Dr. and Mrs. Peter S. Bing Scholarship, the V Foundation for Cancer Research Martin D. Abeloff V Scholar Award, the German Research Foundation Research Fellowship, the Finnish Academy of Sciences Finnish Distinguished Professor Award, the Commonwealth Foundation, Mr. David H. Koch, and the Irving A. Hanson Memorial Foundation.
Scientists participating in this research included Martin Aryee, Julia Engelmann, Philipp Nuhn, Meltem Gurel, Michael Haffner, David Esopi, Rafael Irizarry, Robert Getzenberg, William Nelson, Jun Luo, Jianfeng Xu, and William Isaacs from Johns Hopkins; Wennuan Liu from Wake Forest University; and G. Steven Bova from the University of Tampere in Finland.
Yegnasubramanian, Haffner, Esopi, Nelson, and Isaacs and The Johns Hopkins University have provisional or fully executed patents relating to DNA methylation biomarkers in prostate cancer.? Yegnasubramanian and Nelson, along with The Johns Hopkins University, hold a patent for a polypeptide for detection of methylated DNA.? This reagent has been made available to the research community via a nonexclusive license with Clontech, Inc., which provides royalties to The Johns Hopkins University, Yegnasubramanian, and Nelson from sales of kits containing this reagent.? The authors are pursuing intellectual property protection for the new prostate cancer biomarkers described in this research.
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