Gene variation may elevate risk of liver tumor in patients with cirrhosis

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Growth factor pathway may be target for preventive treatment

A genetic  variation appears to significantly increase the risk that individuals with  cirrhosis of the liver will 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 in the January 2 edition of the Journal of the American Medical Association 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, 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,” says Tanabe, an Associate Professor of Surgery at Harvard Medical School.  “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.”

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.