|Short Strand of RNA May Help Predict Survival and Response to Treatment for Patients with Liver Cancer
A small RNA molecule, known as a microRNA, may help physicians
identify liver cancer patients who, in spite of their poor prognosis,
could respond well to treatment with a biological agent called
interferon. The finding, by scientists at the National Cancer
Institute (NCI), part of the National Institutes of Health, and
their partners at Fudan University, Shanghai, and the University
of Hong Kong in China and at Ohio State University, Columbus,
appeared in the Oct. 8, 2009, issue of The New England Journal
"Interferon is an experimental therapeutic agent
that has been used for many years to treat cancer patients, but
with modest benefit," said study first author Junfang Ji,
Ph.D., of the Liver Carcinogenesis Section at NCI's Center
for Cancer Research.
"Our findings are exciting because we are rediscovering
a drug that may have great potential for patients with a particular
genomic profile. Being able to treat patients with an existing
drug based on a tumor's genomic profile should improve
its efficacy and reduce the cost of treatment," added study
senior author Xin Wei Wang, Ph.D., chief of the Liver Carcinogenesis
Hepatocellular carcinoma, or HCC, is a common type of liver
cancer. Surgery is currently the most effective therapy for this
disease, but only about 10 percent to 20 percent of patients
are eligible for this option, and even among eligible patients
the relapse rate is high. Post-operative (adjuvant) treatment
with interferon often follows surgery in an attempt to prevent
relapse in some patients, but this approach often fails as well.
How HCC develops is unclear. What is known is that it occurs
more often in men than in women, and men tend to develop a more
aggressive form of the disease. Differences in tumor biology
and/or in the tumor microenvironment — the noncancerous tissue
surrounding a tumor — may play a role.
Changes in microRNA levels have been noted in various human
cancers, so a research team led by Wang looked at variation in
the expression of microRNAs involved in HCC. These small RNA
molecules play an important role in controlling gene activity
by regulating a process known as translation. In translation,
another type of RNA molecule, called a messenger RNA (mRNA),
copies the genetic code stored within a gene and carries it to
cellular structures called ribosomes and, once there, serves
as a template to build the cell's proteins. There are many
different types of microRNA, and a single microRNA species can
affect the expression of many different proteins.
The team measured levels of microRNAs associated with both cancerous
and normal tissue in men and women. The researchers analyzed
microRNA expression profiles from 241 surgery patients. By first
comparing the microRNA profiles of normal liver tissue, and then
comparing microRNAs in men and women, the researchers identified
several microRNAs that were expressed more abundantly in normal
female liver tissue. One of these, miR-26, was highly abundant
and showed the greatest difference between the sexes, so it was
chosen for further analysis.
Overall, whether male or female, patients who had low levels
of miR-26 did not live as long as patients who had higher expression
levels of this microRNA. There was about a four-year difference
in survival between the patient groups. The researchers
validated their findings in three independent groups of HCC patients,
and again, those with lower tumor miR-26 levels had poorer survival.
In a separate analysis, the team investigated whether miR-26
status influenced sensitivity to interferon therapy. They examined
the levels of miR-26 in tumor samples collected from 135 patients
who participated in a trial that evaluated interferon therapy
in addition to other standard therapies following surgery. Among
the 72 patients who had received interferon therapy as part of
their cancer treatment, the researchers found that those with
low tumor levels of miR-26 (indicative of a poor prognosis) benefited
from receiving adjuvant interferon therapy. These patients survived
at least 7.7 years longer than patients with low tumor levels
of mi-R-26 that did not receive interferon therapy. In
contrast, patients whose tumors had normal levels of miR-26 did
not benefit from interferon. The researchers also validated their
findings in a separate group of 79 patients.
These findings indicate that miR-26 status in tumors may be
useful information both to determine prognosis for patients with
HCC and to inform the selection of patients who might benefit
from treatment with interferon to prevent disease relapse.
"HCC is an aggressive form of liver cancer and, among
the small fraction of patients who are eligible for surgery,
the rate of recurrence is high," said Wang. "Our
study serves as a proof-of-concept for the use of microRNA expression
levels to identify liver cancer patients who may benefit from
interferon in addition to surgery."
All patients included in the study underwent surgery between
1999 and 2003 at the Liver Cancer Institute of Fudan University
and at the University of Hong Kong Medical Center Centre. Most
of the patients were hepatitis B virus-positive Chinese HCC patients.
The researchers noted that more work will be needed to evaluate
the association of miR-26 status with outcomes in non-Asian HCC
patients. They will also need to examine HCC patients who have
other underlying liver diseases, such as those infected with
hepatitis C virus and/or have cirrhosis related to alcohol abuse.
The research team is planning a prospective trial to further
investigate the benefit of interferon therapy in HCC patients
who have tumors with low levels of miR-26.
For more information on Dr. Wang's research, please go
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Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen
Y, Meltzer PS, Croce CM, Qin L, Man K, Lo C, Lee J, Ng IOL, Tang
Z, Sun H, and Wang XW. MicroRNA expression, survival, and response
to interferon in men and women with liver cancer. The New
England Journal of Medicine. No. 361, Vol. 15.