A buildup of chemical bonds on certain
cancer-promoting genes, a process known as
hypermethylation, is widely known to render cells cancerous
by disrupting biological brakes on runaway
growth. Now, Johns Hopkins scientists say the reverse
process — demethylation, which wipes off those
chemical bonds — may also trigger more than half of
all cancers.
One potential consequence of the new research is that
demethylating drugs now used to treat
some cancers may actually cause new cancers as a side
effect.
"It's much too early to say for certain, but some
patients could be at risk for additional primary
tumors, and we may find that they need a molecular profile
of their cancer before starting
demethylating therapy," said Joseph Califano, professor of
otolaryngology-head and neck surgery and
of
oncology at Johns Hopkins.
The findings, based on studies of normal and cancer
cells from human mouth, nose and throat
tissue, provide more evidence that important regulators of
gene activity occur outside as well as inside
DNA in a cell's nucleus. A report on the work appears on
March 23 in PLoS One.
"While cancer-causing and other mutations alter vital
protein-making pathways by rewriting the
gene's DNA code, epigenetic changes affect genes without
changing the code itself," Califano said.
"The new studies tell us that such changes occur not only
when methyl groups bond to a gene's on-off
switch but also when they come unglued."
Califano said that sporadic reports of demethylation
as a tool in activating cancer-promoting
genes led his team to develop a systematic way to discover
these epigenetic changes and show how the
process is linked to cancer. To gather their evidence,
Califano and his group treated two cell lines
from normal oral tissue with the demethylating drug
5-azacytidine and collected a list of genes that
were activated as a result. They used special silicon chips
carrying pieces of genetic material that
allow thousands of genes to be analyzed at one time to
locate genes activated by demethylation.
The list was cross-referenced with genes "turned on"
in 49 head and neck cancer samples and 19
normal tissue samples. In all, Califano and his team found
106 genes specific to head and neck cancer
that were activated by the demethylation process. "Some of
the genes regulate growth, others
metabolize sugars, and some have already been linked to
cancer development," Califano said.
Further analysis by the Johns Hopkins team revealed a
single connection among 106 genes:
Methylation within them is regulated by another gene called
BORIS. BORIS acts as a "master
regulator," recruiting other proteins to demethylate a
coordinated set of genes and signaling the
development of cancer. According to the scientists, nearly
60 percent of a wide range of cancers,
including head and neck and lung cancer, have high levels
of BORIS expression.
Califano said he envisions that agents like
5-azacytidine may need to be combined with a
"BORIS blocker," a drug that has yet to be developed, to
protect patients who need demethylating
therapies.
The research is funded by the Flight Attendant Medical
Research Institute, National Institute
of Dental and Craniofacial Research and National Cancer
Institute.
Research participants were Ian M. Smith, Chad A.
Glazer, Suhail K. Mithani, Michael F. Ochs,
Wenyue Sun, Sheetal Bhan, Andrew Gray, Chunyan Liu, Steven
S. Chang, Kimberly L. Ostrow, William
H. Westra, Shahnaz Begum and Mousumi Dhara, all of Johns
Hopkins; and Alexander Vostrov, Ziedulla
Abdullaev and Victor Lobanenkov, all of the National
Institutes of Health.
Califano maintains a clinical practice at Johns
Hopkins Head and Neck Surgery at Greater
Baltimore Medical Center; the Milton J. Dance Jr. Head and
Neck Center, also at GBMC; and The
Johns Hopkins Hospital.
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