Tracing liver cancer’s genetic signature

By Haley Bridger, Broad Communications, October 15th, 2008
photomicrograph of adjacent liver sectionsThe genetic signature found in adjacent liver cells can predict survival and liver cancer recurrence.
Image courtesy of Bang Wong

Millions of tissue samples collected from cancer patients over the last century may hold valuable clues about what makes tumors grow and why they so often return. The ways these samples are preserved, however, have frustrated efforts to probe them at a molecular level. Researchers from the Broad Institute and other institutions around the world have developed a promising technique, which they have applied to one of world’s most deadly cancers: hepatocellular carcinoma. This approach helped them unearth a signature written in the genetic code of tissue surrounding liver tumors that could help predict how well patients with the illness will fare.

Liver cancer, or hepatocellular carcinoma (HCC), is the third most lethal cancer worldwide. Cancer recurs in many liver cancer patients, but scientists have uncovered only a few molecular clues about how the disease progresses and why the cancer often comes back. However, the new research reveals that genes expressed in liver tissue adjacent to a tumor may hold clues about the likelihood of recurrence. A distinct genetic signature, or unique pattern of gene activity, that the researchers have found in the surrounding tissue could someday help physicians determine the proper course of preventative treatment for a patient.

The researchers’ discovery of this prognostic factor would not have been possible without a suitable method for profiling tissue samples. Medical facilities have been primarily preserving samples for the last 100 years as formalin-fixed paraffin-embedded (FFPE) tissue samples. “In most hospitals and clinics, the prevailing method of storing patient tissue involves a chemical fixative, which often precludes future genome-scale analyses. That means the vast majority of patient samples have effectively been off-limits to a variety of important questions,” said senior author Todd Golub, who directs the Cancer Program at the Broad Institute of MIT and Harvard and is the Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute.

Techniques have been developed to conduct genome-scale scans on tissue that has been frozen instead of chemically preserved with the FFPE method, but freezing tissue is a new approach and the supply of frozen samples is limited. Having large-scale access to the genomic information stored in chemically preserved samples would be ideal. “Our work reveals that it is indeed possible to access this biological trove, a step we hope will bolster future genomic discoveries throughout the scientific community,” said Golub.

To do so, researchers led by Golub and Josep Llovet of the Mount Sinai School of Medicine and Hospital Clínic Barelona designed a profiling technique capable of analyzing thousands of genes. This new approach revealed the genetic signature in neighboring tissue. Their results appeared in the advanced online issue of the New England Journal of Medicine on October 15.

According to Llovet, this new technique could have a significant impact on oncology research as well as other medical studies. Currently, it may take years for researchers to attain enough fresh, frozen samples to complete a study, but with access to archived, FFPE samples, that timeline could be significantly shortened. “With this novel assaying technique, it will be possible to explore at a molecular level all types of tumors and other diseases that were previously impossible to explore because not enough tissue samples were available,” Llovet said. “This assay is a huge advancement for medicine.”

After detecting the genetic signature in adjacent liver tissue, the researchers hypothesized that instead of recurring from primary tumor cells, new tumors develop in HCC patients because the liver itself is damaged. This development of new tumors in a damaged organ is known as the field effect. That means that, for the first time, a gene signature is able to capture the field effect in HCC, and identifies those patients at high risk of developing new tumors — information that may bolster the design of surveillance strategies and chemopreventive therapies.

“It’s not sufficient to only look at the primary tumor,” said Yujin Hoshida, a postdoctoral associate at the Broad Institute and first author of the paper. “Our research indicates that the field effect is more predictive of liver cancer patient outcome than the characteristics of the primary tumor.”

The new findings could spur advancements in patient care. In the future, if physicians are able to use the genetic signature to identify liver cancer patients most at risk for recurrence, they may be able to implement aggressive treatment strategies to prevent tumors from reoccurring or place this group under careful surveillance to help detect new tumors early. In addition, trials targeting only those at risk of tumor recurrence could help zero in on drugs that are most effective for those who stand to benefit most from preventative measures.

In addition to Hoshida and Golub, other researchers from the Broad who contributed to this work include Derek Chiang, Amy Camargo, Supriya Gupta, Jamie Moore, Matthew Wrobel, Jim Lerner, Michael Reich, Jennifer Chan, and Stacey Gabriel. Also contributing to this paper are researchers from the following institutions: Dana-Farber Cancer Institute, Mount Sinai School of Medicine, Toranomon Hospital, Brigham and Women’s Hospital, Institut d’Investigacions Biomediques August Pi i Sunyer, and the Howard Hughes Medical Institute.

Paper(s) cited: 
Hoshida Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. New England Journal of Medicine DOI: 10.1056/NEJMoa0804525.