Gene Variation May Elevate Risk Of Liver Tumor In Patients With Cirrhosis

January 3, 2008

ScienceDaily (Jan. 2, 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. 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 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 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.

This research was published in the January 2 issue of JAMA.

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, Chung, MD,

Lauwers, MD, Yakup Kulu, Alona Muzikansky, Darshini Kuruppu, PhD,

Lanuti, MD, Goodwin and Fuch, PhD, of the MGH; and

Antoinette Lemoine, MD, and Azoulay, MD, PhD, Brousse Hospital,

Paris.

Adapted from materials provided by Massachusetts General Hospital.

http://www.sciencedaily.com/releases/2008/01/080101184640.htm

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January 3, 2008