Johns Hopkins Gazette | April 20, 2009
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The newspaper of The Johns Hopkins University April 20, 2009 | Vol. 38 No. 31
Autopsy Study Links Prostate Cancer to Single Rogue Cell

By Vanessa Wasta
Johns Hopkins Medicine

One cell, one initial set of genetic changes — that's all it takes to begin a series of events that lead to metastatic cancer. Now, Johns Hopkins experts have tracked how the cancer process began in 33 men with prostate cancer who died of the disease. Culling information from autopsies, their study points to a set of genetic defects in a single cell that are different for each person's cancer.

"These were not your average autopsies," said pathologist G. Steven Bova, assistant professor of pathology at Johns Hopkins. "We dissected every bit of tumor — in the primary and metastatic sites — and recorded exactly where each piece of tissue came from, analyzed it and databased the findings." In total, Bova estimates that he and his colleagues examined 150,000 slides and 30,000 blocks of tissue.

The study took 14 years to complete, and part of the challenge was in finding men living with prostate cancer who would agree to have their bodies autopsied immediately after they died. "Many of the men were motivated to join the study in hopes of leaving some legacy that might lead to cures for this cancer," said Bova, who holds secondary appointments at Johns Hopkins in the departments of Pathology, Genetic Medicine, Health Sciences Informatics, Oncology and Urology.

"Much is unclear and appears chaotic about how cancer spreads, but analyzing genetic markers allows us to trace its roots backward, somewhat like ancestry," Bova said. Results of the study were published online April 12 in Nature Medicine.

Clues to finding the genetic culprit for cancer spread are hidden in the changes that occur in a cell's DNA, the alphabetical code made up of chemicals that guide the everyday life of a cell. Cancers are caused by alterations in DNA code that occur in a variety of ways: making errors in the nucleotide alphabet through mutations, changing the balance of chemicals attached to the on/off switches of genes and altering the number of gene copies in a cell. When the number of gene copies is disrupted in a cell beyond the customary two copies — one inherited from each parent — a gene's function can be damaged. This process, called copy number variation, can set the stage for unchecked cell growth and spread, a hallmark of cancer.

For this study, the investigators scanned genes spanning the whole genome in the autopsy samples looking for areas of copy number variation. They did this by attaching the DNA to special silicon chips, and then photographed them with a computer program that produces a report with varying colors representing the amount of DNA in the sample.

The scientists compared the patterns of gains and losses in tissue samples from multiple metastatic sites in 29 of the men. Unique copy number changes were identified, as well as ones that were shared between multiple metastatic sites in each man and with other men in the study.

For example, in several men the investigators found cells in different areas of metastasis that contained missing chunks of DNA in one common region of the genome. The exact location of the DNA loss was different for each man, but all occurred in the same DNA region. "Each person has a different set of defects that contributes to the cancer," Bova explained.

Metastatic sites develop from cancer cells that break off of the primary cancer. If cancer cells at more than one metastatic site carry a common set of nonrandom genetic defects, it is likely that these cells are derived from a single parent cell, Bova said. Tissue samples from 14 of the 33 men were studied at the highest available resolution, and all showed common genetic patterns across metastatic sites, suggesting a single cell source for their cancer.

Bova said that future studies will help determine whether the common set of changes shared by the various metastatic sites arose all at once in the prostate or if the changes accumulated more slowly over time.

Bova said that such autopsy studies of metastatic cancer can provide a molecular catalog of cellular defects specific to individuals and general groups. The findings, he said, could help narrow the focus of research and guide personalized cancer therapy.

The research was funded by the Pirkanmaa Cancer Foundation, Maud Kuistila Foundation, Finnish Medical Foundation, Medical Research Fund of Tampere University Hospital, Academy of Finland, Cancer Society of Finland, Reino Lahtikari Foundation, Sigrid Juselius Foundation, CaPCURE Foundation, John and Kathe Dyson, David Koch, National Cancer Institute, Prostate Cancer Research and Education Foundation, U.S. Department of Defense Congressionally Directed Prostate Cancer Research Program, Grove Foundation and the American Cancer Society.

In addition to Bova, research participants from Johns Hopkins were Jeanne Kowalski, Charles M. Ewing, Mario A. Eisenberger, Michael A. Carducci, William G. Nelson, Srinivasan Yegnasubramanian, Jun Luo and William B. Isaacs.

Video of Bova discussing the study can be found at


Related Web sites

G. Steven Bova's blog
'Nature Medicine'


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