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Genetic analysis predicts whether liver cancer likely to recur
October 16, 2008New technology makes it possible to study tissue samples locked away for decades
Researchers are poised to unlock the genetic secrets stored in hundreds of thousands of cancer biopsy samples locked in long-term storage and previously thought to be useless for modern genetic research. With the aid of a new technique developed by Howard Hughes Medical Institute researchers, scientists can now reconstruct thousands of genes that are "shredded" into tiny pieces when tissue samples are treated with a chemical fixative and stored in wax - a protocol that is commonly used to preserve the samples.
The scientists tested their new technique on liver tissue samples from 307 patients enrolled in clinical studies in four different countries. Using sophisticated microarray technology, the scientists studied RNA from stored liver tissue samples and identified a tell-tale genetic profile that indicates whether liver cancer will recur. Since the testing was done on tissue samples of patients whose clinical outcome was known, the researchers were able to associate specific "gene expression signatures" with particular outcomes.
The researchers are optimistic that oncologists will be able to use this information to determine which liver cancer patients would likely suffer recurrence and treat them to help prevent it.
"It is now possible to scan the entire genome for gene expression profiles in tissues that have been fixed for a very long time-in our study as long as twenty-four years," said Howard Hughes Medical Institute investigator Todd R. Golub, who led the study. "There are lots of those tissues available compared with frozen ones, and tissue availability has been a real bottleneck in cancer genomic research."
The findings were published October 15, 2008, in an advance online article in the New England Journal of Medicine by an international team including collaborators from Japan, Spain, Norway and Italy.
For decades, hospitals have stored tissue samples from biopsies and surgeries by soaking them in a combination of formaldehyde and water (called formalin) and then embedding them in wax. However, this type of storage breaks down the genetic material into pieces that are so small that they are essentially useless for genetic studies, explained Golub, a researcher at the Dana-Farber Cancer Institute and the Broad Institute of the Massachusetts Institute of Technology and Harvard University.
Golub's research is based on the premise that extraordinary insights into the molecular basis of cancer can be obtained by taking global views of the genomes of patient-derived tumor samples. To broaden the view of cancer genomes, Golub and his colleagues use DNA microarrays (DNA chips) to monitor the gene expression (gene activity) of thousands of genes simultaneously across the human genome. This technique, pioneered by HHMI investigator Patrick Brown at Stanford University, involves extracting messenger RNA (mRNA) from tumor samples fluorescent labeling and hybridization to an array of DNA probes in the DNA chip. By measuring the mRNA levels from each gene, researchers can determine the activity of the gene in the tumor.
"On average, mRNA samples in fresh tissue are around two thousand bases long," said Golub said. "But when a tissue sample is fixed in formalin, the mRNA gets cleaved into little bits between fifty and one hundred bases long. So, these samples are not amenable to conventional microarray technology."
However, scientists at Illumina, Inc., in San Diego, had recently developed a way to perform gene expression analysis on these degraded samples. The company had successfully used their technique to study the expression levels of several hundred genes in formalin-fixed samples. "We reasoned that it might work for analyzing the entire genome," Golub said.
To find out, Golub's team looked at tissue samples from 307 patients enrolled in liver cancer studies in Tokyo, Milan, New York and Barcelona. They first analyzed samples of the tumors themselves, looking for gene expression patterns that might be predictive of cancer recurrence. "You would think that if you wanted to learn about a tumor's probability of coming back, you would look at the genomic profile of the tumor," he said. "But we found that the genetic profile of the tumor wasn't predictive of outcome, survival, or late recurrence."
However, the paper's first author, Yujin Hoshida, suggested that they also analyze gene expression in what appeared to be normal liver tissue adjacent to the tumor. Hoshida knew that liver cancer researchers have been debating a hypothesis that a "field defect" of the whole liver may predispose a person to liver cancer. That theory posits that liver tissue that appears normal might in fact harbor detectable genetic abnormalities that would give rise to new tumors after the main tumor was removed. Analysis of this adjacent tissue revealed a characteristic gene expression signature in 186 genes that reliably correlated with a high frequency of tumor recurrence.
"These findings indicate that we might be able to identify patients at risk of recurrence and target those patients with interventions to help prevent it," he said. "The fact that the predictive information comes not from the tumor but from surrounding tissue could offer important insights into the mechanism of liver cancer."
More broadly, said Golub, this analytical technique could be applied to any type of cancer. "We don't know whether there will be a recurrence signature in the non-tumor tissue, of, for example, breast cancer," he said. "But it is now possible to explore that possibility." Golub noted that the technique opens the way for genomic study of fixed tissue samples in diseases, such as multiple sclerosis.
In an accompanying editorial in the same issue of the NEJM, Morris Sherman of the University of Toronto wrote that the findings "bring the possibility of individualized therapy for hepatocellular carcinoma one step closer." He wrote that the new research "has opened the door to identifying the relevant gene expression in the pathogenesis of hepatocellular carcinoma as it evolves from non-tumorous liver, as well as possibly initiating research into a molecular method for determining more precisely who is at risk for the development of hepatocellular carcinoma."
Golub said the next step is to analyze samples from more patients to confirm findings in liver cancer. He said he sees no major barriers to translating the findings into a clinical diagnostic technique, but some technical issues remain to be resolved.
Howard Hughes Medical Institute
The researchers are optimistic that oncologists will be able to use this information to determine which liver cancer patients would likely suffer recurrence and treat them to help prevent it.
"It is now possible to scan the entire genome for gene expression profiles in tissues that have been fixed for a very long time-in our study as long as twenty-four years," said Howard Hughes Medical Institute investigator Todd R. Golub, who led the study. "There are lots of those tissues available compared with frozen ones, and tissue availability has been a real bottleneck in cancer genomic research."
The findings were published October 15, 2008, in an advance online article in the New England Journal of Medicine by an international team including collaborators from Japan, Spain, Norway and Italy.
For decades, hospitals have stored tissue samples from biopsies and surgeries by soaking them in a combination of formaldehyde and water (called formalin) and then embedding them in wax. However, this type of storage breaks down the genetic material into pieces that are so small that they are essentially useless for genetic studies, explained Golub, a researcher at the Dana-Farber Cancer Institute and the Broad Institute of the Massachusetts Institute of Technology and Harvard University.
Golub's research is based on the premise that extraordinary insights into the molecular basis of cancer can be obtained by taking global views of the genomes of patient-derived tumor samples. To broaden the view of cancer genomes, Golub and his colleagues use DNA microarrays (DNA chips) to monitor the gene expression (gene activity) of thousands of genes simultaneously across the human genome. This technique, pioneered by HHMI investigator Patrick Brown at Stanford University, involves extracting messenger RNA (mRNA) from tumor samples fluorescent labeling and hybridization to an array of DNA probes in the DNA chip. By measuring the mRNA levels from each gene, researchers can determine the activity of the gene in the tumor.
"On average, mRNA samples in fresh tissue are around two thousand bases long," said Golub said. "But when a tissue sample is fixed in formalin, the mRNA gets cleaved into little bits between fifty and one hundred bases long. So, these samples are not amenable to conventional microarray technology."
However, scientists at Illumina, Inc., in San Diego, had recently developed a way to perform gene expression analysis on these degraded samples. The company had successfully used their technique to study the expression levels of several hundred genes in formalin-fixed samples. "We reasoned that it might work for analyzing the entire genome," Golub said.
To find out, Golub's team looked at tissue samples from 307 patients enrolled in liver cancer studies in Tokyo, Milan, New York and Barcelona. They first analyzed samples of the tumors themselves, looking for gene expression patterns that might be predictive of cancer recurrence. "You would think that if you wanted to learn about a tumor's probability of coming back, you would look at the genomic profile of the tumor," he said. "But we found that the genetic profile of the tumor wasn't predictive of outcome, survival, or late recurrence."
However, the paper's first author, Yujin Hoshida, suggested that they also analyze gene expression in what appeared to be normal liver tissue adjacent to the tumor. Hoshida knew that liver cancer researchers have been debating a hypothesis that a "field defect" of the whole liver may predispose a person to liver cancer. That theory posits that liver tissue that appears normal might in fact harbor detectable genetic abnormalities that would give rise to new tumors after the main tumor was removed. Analysis of this adjacent tissue revealed a characteristic gene expression signature in 186 genes that reliably correlated with a high frequency of tumor recurrence.
"These findings indicate that we might be able to identify patients at risk of recurrence and target those patients with interventions to help prevent it," he said. "The fact that the predictive information comes not from the tumor but from surrounding tissue could offer important insights into the mechanism of liver cancer."
More broadly, said Golub, this analytical technique could be applied to any type of cancer. "We don't know whether there will be a recurrence signature in the non-tumor tissue, of, for example, breast cancer," he said. "But it is now possible to explore that possibility." Golub noted that the technique opens the way for genomic study of fixed tissue samples in diseases, such as multiple sclerosis.
In an accompanying editorial in the same issue of the NEJM, Morris Sherman of the University of Toronto wrote that the findings "bring the possibility of individualized therapy for hepatocellular carcinoma one step closer." He wrote that the new research "has opened the door to identifying the relevant gene expression in the pathogenesis of hepatocellular carcinoma as it evolves from non-tumorous liver, as well as possibly initiating research into a molecular method for determining more precisely who is at risk for the development of hepatocellular carcinoma."
Golub said the next step is to analyze samples from more patients to confirm findings in liver cancer. He said he sees no major barriers to translating the findings into a clinical diagnostic technique, but some technical issues remain to be resolved.
Howard Hughes Medical Institute
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