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Gene variation may elevate risk of
liver tumor in patients with cirrhosis
Growth factor pathway may
be target for preventive treatmen
BOSTON - January 1, 2008 - A particular gene variation appears
to significantly increase the risk that individuals with cirrhosis
of the liver will go on to develop hepatocellular carcinoma (HCC),
a liver tumor that is the third leading cause of cancer death. In
the January 2 Journal of the American Medical Association,
researchers from Massachusetts
General Hospital (MGH) Cancer Center and colleagues in France
describe finding that a single alteration in the epidermal growth
factor (EFG) gene may greatly increase the risk of developing HCC.
"If these results are confirmed, this EGF variation could be
used to determine which cirrhotic patients should be screened more
intensively for tumor development," says Kenneth Tanabe, MD,
chief of Surgical Oncology at the MGH Cancer Center, the study's
lead author. "In addition, the molecular pathway controlled
by EGF and its receptor EGFR - which is known to be important in
several types of cancer - appears to be an excellent target for
chemoprevention studies. This is a deadly cancer and so progress
in prevention and early detection is critically important."
HCC is the sixth most common solid tumor worldwide and most commonly
develops in individuals with cirrhosis, which may be caused by infection
with the hepatitis B or C viruses. There are currently no effective
treatments for most HCC patients, so there is considerable interest
in strategies that may prevent development of the tumor.
EGF's normal function is to stimulate tissue growth. Animal studies
have shown that elevated levels of this protein in the liver lead
to tumor development and that blocking the protein's receptor can
prevent development of liver cancer. The current study was designed
to determine whether cirrhotic patients with higher EGF levels are
at greater risk for liver cancer and to determine the influence
of a particular inherited gene on EGF levels in cirrhotic patients.
The researchers focused on a known variation in the EGF gene - the
presence of the nucleotide guanine (G) instead of the more common
adenine (A) in a particular location - which has been shown to increase
EGF secretion in blood cells and raise the risk for malignant melanoma.
Individuals inherit one copy of the gene from each parent and therefore
have this gene with either two copies of A (A/A), two copies of
G (G/G), or one copy of each (A/G). Genetic analysis of liver tumor
cell lines showed that messenger RNA transcribed from DNA strands
with the G allele was more stable that that transcribed from the
A version, which could explain why cells with two G copies tend
to secrete higher levels of EGF.
The researchers then studied tissue samples from all patients in
the MGH Cancer Center Tumor Bank who had cirrhosis. Among the 207
patients with cirrhosis, most of whom were infected with the hepatitis
C virus, 59 also had HCC. Patients with at least one copy of the
G nucleotide had a significantly higher risk of developing HCC than
did A/A patients - ranging from a more than twofold increase for
those with one G to an over fourfold increase for those with two
G alleles. In all three genotypes, tissue analysis showed that EGF
levels were highest in the G/G patients, as was activation of the
EGFR receptor. In addition, blood levels of EGF were highest in
those with two copies of the G allele .
To confirm these finding in a different patient population, the
MGH team worked with colleagues from the Paul Brousse Hospital in
Paris. Samples from this group, all of whom had alcoholic cirrhosis,
also showed that patients with the G/G version of the EGF gene had
a significantly greater risk of developing the liver tumor than
did the A/A patients, in this instance an almost threefold risk
increase.
In both the MGH and French study groups, controlling for factors
such as age and gender did not change the increased risk associated
with the G allele. While both groups primarily consisted of Caucasian
patients, in the MGH group, it was noted that the G allele was more
common among Asian patients; and it is well known that more than
half the cases of HCC worldwide occur in China.
"We now need to prospectively study EGF levels in cirrhotic
patients, to see if elevated levels will correlate with a greater
risk of developing HCC, and look at factors such as diet, drugs
or ethnicity that may modulate EGF levels," Tanabe says. "I
think this is a terrific opportunity to see if targeting a specific
pathway will prevent HCC in this group of patients, who are at risk
for liver cancer because of their cirrhosis." Tanabe is an
associate professor of Surgery at Harvard Medical School.
The study was supported by grants from the National Institutes
of Health, the MGH Department of Surgery, Tucker Gosnell Gastrointestinal
Cancer Center, and the Fund for Medical Discovery. Co-authors of
the JAMA article are Dianne Finkelstein, PhD, Hiroshi Kawasaki,
Tsutomu Fujii, MD, PhD, Raymond Chung, MD, Gregory Lauwers, MD,
Yakup Kulu, Alona Muzikansky, Darshini Kuruppu, PhD, Michael Lanuti,
MD, Jonathan Goodwin and Bryan Fuch, PhD, of the MGH; and Antoinette
Lemoine, MD, and Daniel Azoulay, MD, PhD, Paul Brousse Hospital,
Paris.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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