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Gene Signature for Liver Cancer Recurrence Found

A 186-gene panel, discovered in normal cells surrounding the tumor, may predict cancer survival, new research contends

WEDNESDAY, Oct. 15, 2008 (HealthDay News) -- Researchers have identified a new genetic signature that may predict whether a liver tumor is likely to recur, according to a new study.

Unlike other such signatures that have been identified for other cancers, this one has something of a flourish: It is hidden not within the tumor itself, but in the normal cells that surround it -- and which, by inference, remain in the body following surgery.

The findings potentially open the door to new surveillance, treatment, and intervention strategies for liver cancer patients, both after surgery and possibly before the primary cancer ever arises, experts said.

"I think this is the start of a big step forward," said Dr. Morris Sherman of the University of Toronto, who wrote an editorial that accompanied the research, which was released online Wednesday by the New England Journal of Medicine. "It will really make a major difference in the way we monitor patients at risk for liver cancer -- potentially. I mean, there are lots of pitfalls in the way, but that's what it promises."

Dr. Todd Golub, of the Broad Institute of the Massachusetts Institute of Technology, and Dr. Josep Llovet, of Mount Sinai School of Medicine in New York City, led the study, which also involved scientific teams in Japan, Italy, Norway and Spain.

The researchers in this study faced a significant technical hurdle. Most gene-expression profiling studies use tissue samples that have been flash frozen. But tissues taken in biopsies are usually chemically fixed and embedded in wax. That method preserves the tissue, making it easier for pathologists to examine, but it also renders the nucleic acids -- especially RNA -- difficult to extract.

Golub, Llovet, and their team were able to circumvent this problem by implementing techniques for extracting nucleic acids from wax-encased tissues, some dating back 24 years, and then using those materials to probe the expression of 6,000 human genes. They then focused on which genes' expression levels correlated with a recurrence at least two years after surgery, and also with survival. From all that, they came up with a list of 186 genes as the signature for liver cancer recurrence.

Assuming the list is validated, clinicians could conceivably use it to test liver biopsies to determine whether an individual is likely to have a cancer recurrence, and perhaps guide treatment accordingly, experts say. It might even be possible to predict whether a person will develop liver cancer in the first place based on this same signature.

Lead researcher Llovet believes that because wax-encased tissue can now be used in broader analyses, "you have access to millions and millions of samples in order to explore specific molecular alterations. And I think this is one of the breakthroughs of the paper."

According to Dr. Arul Chinnaiyan of the University of Michigan Medical School, an expert on gene expression analysis of cancer tissue, the observation that a gene signature that predicts cancer recurrence occurs outside the tumor tissue itself could be a novel finding.

"Most of the [genetic profiling] studies that have been published have been predicting prognosis using the tumor cells themselves, not the surrounding cells," Chinnaiyan said. "In this particular case, it was sort of reversed: The tumor cell itself didn't predict [outcome], but the surrounding cells did."

According to Sherman, this apparent paradox -- how can normal cells excised from the body know what will happen more than two years later? -- can be explained through what oncologists call the "field effect."

Most liver cancer is caused by hepatic viruses. If one such virus infects the liver, it induces a mutation in a liver cell, giving that cell a growth advantage that enables it to outcompete its neighbors. Though this cell is not yet cancerous, its progeny nevertheless begin to take over the tissue. And, if another mutation arises by chance in one of those progeny cells, that cell gains an additional growth advantage, enabling it to compete even more effectively in the liver.

As much as 50 percent of some infected liver tissue may be built of such noncancerous, "clonal" populations, Sherman said.

Proliferating at an accelerated rate, these cells are essentially primed for cancer. Though a normal cell requires a number of molecular changes to become cancerous, these clonal liver cells are already halfway there; it would not take many more mutations to push them over the edge to cancer. This is the field effect.

"It is certainly intriguing data," Chinnaiyan said. Though he cautioned that much work remains before the findings can be applied in the clinic in the form of diagnostics, he added, "It certainly has potential. Based on the traction that similar sorts of expression signature-based tests have had, I think it certainly has possibilities."

According to statistics from the National Cancer Institute, there will be about 21,000 new cases of liver and bile duct cancer diagnosed in the United States this year, and 18,500 deaths.

More information

For more about liver cancer, visit the National Cancer Institute.

SOURCES: Morris Sherman, M.B., Ph.D., associate professor of medicine, University of Toronto; Arul M. Chinnaiyan, M.D., Ph.D., director, Michigan Center for Translational Pathology, and investigator, Howard Hughes Medical Institute, and S.P. Hicks Endowed Professor of Pathology, University of Michigan Medical School, Ann Arbor; Josep Llovet, M.D., director, HCC Research Program, and associate professor of medicine, Mount Sinai School of Medicine, New York City; Oct. 15, 2008, online edition, Nov. 6, 2008, print edition, New England Journal of Medicine
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