Researchers from Massachusetts General Hospital have found that a single nucleotide polymorphism (SNP) - a change in a single unit of DNA - in the epidermal growth factor (EGF) gene may significantly increase the likelihood that a patient with cirrhosis will develop hepatocellular carcinoma (HCC).

HCC is difficult to treat and most commonly arises in patients with cirrhosis, often caused by chronic infection with the hepatitis B or C viruses. The results of this study, published in the January 2 Journal of the American Medical Association, may help identify a subset of patients who would benefit from intensified screening and possibly chemoprevention strategies.

The investigators focused on a SNP in the EGF 61*G allele, in which one or both copies of a specific adenine nucleotide (A) in the EGF gene are replaced with a guanine nucleotide (G). Previous work in both cell cultures and animal models showed that this SNP plays a role in raising EGF protein levels, and EGF has been implicated in liver tumor formation in animals.

"We deliberately chose to focus on one SNP that had previous data suggesting that it's functional" in carcinogenesis, explained Dr. Kenneth Tanabe, lead author of the paper.

The researchers examined DNA from all 207 patients with cirrhosis who had blood or tissue stored in the Massachusetts General Hospital Cancer Center Tumor Bank between 1999 and 2006. Of these patients, 59 developed HCC.

Patients with one copy of the SNP (A/G genotype) were more than two times as likely to develop HCC, and patients with two copies (G/G genotype) were four times as likely to develop the cancer as patients with the A/A genotype. These associations remained significant even after adjusting for age, sex, race, and cause and severity of cirrhosis. The researchers found correspondingly higher EGF and phosphorylated EGF receptor (EGFR) levels in the liver and serum of patients with the G/G genotype.

Collaborators at the Hôpital Paul Brousse in France provided genetic data for a validation study, from 121 white patients with alcoholic cirrhosis seen between 1993 and 2006. Forty-four of those patients later developed HCC.

As in the Massachusetts population, patients with the G/G genotype were significantly more likely to develop HCC - in this case almost three times as likely - than patients with the A/A genotype.

Although "prospective studies examining larger populations of patients…and the application of these observations to ethnic minorities," are needed, explain the authors, they remain intrigued by the possibilities for HCC screening and prevention.

"Identification of molecular markers associated with an increased risk of hepatocellular carcinoma would better define populations at highest risk…and may additionally define important therapeutic targets for prevention and treatment," they state. "Our findings…provide rationale for examination of the EGF-EGF receptor pathway as a novel target for chemoprevention in humans."

Dr. Tanabe's laboratory has begun preliminary work to look for a chemoprevention agent nontoxic enough for long-term use. "We're already looking at the EGF-EGFR pathway using in vitro transformation models to screen potentially clinically useful compounds that would inhibit transformation, and are also developing similar animal models. Setting up those platforms for drug discovery and drug testing could go in parallel with a confirmatory study…It happens to be that a SNP modulates serum EGF levels [in this study], but of course there may be many, many other things that modulate EGF levels," he concluded.

—Sharon Reynolds