Researchers at the
Johns
Hopkins Kimmel Cancer Center have uncovered clearly
recognizable
genetic alterations in tumors and tissue removed from
patients with early-stage lung cancers that look
like good predictors of which of these cancers are more
likely to recur.
The discovery, they say, could change the approach to
treating even the smallest lung cancers —
those the size of a pea — that are known to recur
within five years in 30 percent to 40 percent of
patients.
"This is DNA forensics for cancer," said Malcolm
Brock, associate professor of surgery
in the
Johns Hopkins School of Medicine. "While there may be no
trace of cancer that we can spot after
surgery with a microscope, the DNA evidence from these
tumors may have been left at the scene,
especially in lymph nodes."
The particular molecular flags the team identified are
chemicals known as methyl groups that
latch onto the DNA ladder structure of a gene. Methylation
is a commonly known phenomenon in the
formation and development of cancers because these
chemicals serve as signals to cells to switch
certain genes on or off. Disruption in these signals may
create a cascade of abnormal proteins that
lead to cancer or its recurrence.
In the study published in the March 13 issue of the
New England Journal of Medicine, Brock and
his team report how they combed through more than 700
surgical samples from 167 early-stage, non-
small-cell lung cancer patients searching for specific
methylation patterns linked to the disease.
Tumor and lymph node tissue from 51 patients whose
cancers recurred within 40 months were
compared with samples from the remaining 116 patients,
whose cancers did not recur.
The scientists tested all the samples for methylation
on seven genes linked to the development
of lung cancer. Four of them — p16, H-cadherin, APC
and RASSF1A — showed the highest amounts of
methylation in patients whose cancers recurred.
For many of the genes, the study revealed a twofold
difference in methyl marks between
recurrent cancers and those that did not return.
"The DNA evidence we see for many of the recurring
cases suggests it may be wise, if our work
is confirmed, to reclassify such cancers as advanced
disease instead of early stage," Brock said.
Brock and his colleagues also found that cancers
returned even more swiftly than average for 11
patients who had higher than normal methylation in a deadly
combination of two genes known as p16
and H-cadherin located in both tumor tissue and a lymph
node distant from the original tumor area.
Eight of the 11 patients with this methylation pattern had
cancers that returned within a year. By 30
months, the remaining three patients' cancer also had
recurred.
The investigators did analyze the results to quantify
the odds that a particular patient's cancer
would recur, noting a five- to 25-fold increase in risk
depending on the particular methylation pattern.
They caution that while some of the gene markers lack
statistical significance because of small sample
size, odds predictions are valid for the two most promising
genes, p16 and H-cadherin.
Kimmel Center medical oncologist James Herman says
that if these results are confirmed, the
findings may lead doctors to consider treating high-risk
patients more aggressively with chemotherapy
after surgery. He also said he believes that therapies that
target these gene patterns by stripping
off methyl groups hold promise as well. "These marks of
aggressive disease also are themselves
targets for therapy," he said.
Additional studies of the methyl markers are under way
on lung cancer patients currently being
treated at Johns Hopkins.
Cure rates for lung cancer are far lower than for
other common cancers such as breast or
prostate. Lung cancer is the deadliest cancer and second
most common in the United States.
Funding for the study was provided by the National
Cancer Institute's Specialized Program of
Research Excellence, known as SPORE, Commonwealth
Foundation for Cancer Research, Hodson Trust
and OncoMethylome Sciences.
Additional research participants are Craig M. Hooker,
Emi Ota-Machida, Yu Han, Mingzhou Guo,
Stephen Ames, Sabine Glockner, Steven Piantadosi, Edward
Gabrielson, Genevieve Pridham, Kristin
Pelosky, Stephen C. Yang and Stephen B. Baylin, all of
Johns Hopkins; and Steven A. Belinsky, of the
Lovelace Respiratory Research Institute.
Herman and Baylin are consultants to and receive
research support from OncoMethylome
Sciences. Under a licensing agreement between The Johns
Hopkins University and OncoMethylome,
methylation-specific PCR was licensed to OncoMethylome, and
the researchers are entitled to a share
of the royalties received by the university from sales of
the licensed technology. Brock receives
research support from OncoMethylome Sciences.
GO TO