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
www.youtube.com/JohnsHopkinsKimmel.
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