Understanding East vs. West

Largest genomic study of liver cancer identifies mutations that distinguish Asian and Western disease

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HOUSTON—Taking a small step toward eventually developing tailor-made treatments for liver cancer patients, the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC) conducted the largest study of the genomes of liver tumors, identifying a mutation signature that contributes more to cases of the disease in Japanese males than in men of European ancestry, an international consortium of researchers stated in a report online in the journal Nature Genetics.
“The novelty of this study involves associating mutation patterns with different ethnic groups,” said Dr. David Wheeler, a professor in the BCM-HGSC and a corresponding author of the report. Researchers from the University of Tokyo, Japan’s National Cancer Center Research Institute (NCCRI) and the National Cancer Center Hospital in Tokyo (NCC) also participated on this work.
“Patients are subject to different environmental factors, or they are genetically different,” said Wheeler, a member of the National Cancer Institute-designated Dan L. Duncan Cancer Center at Baylor. “The profiles of the tumors were not associated with hepatitis B, hepatitis C or cirrhosis—known environmental factors associated with hepatocellular carcinoma (liver) cancers.”
“Our results give us new insights into the induction and progression of liver cancer,” Wheeler tells DDNews. “It has been known for a long time that the incidence of different cancers varies from one country to the next. Having a large, multiracial study enabled us to explore the differences in disease between populations at the molecular level. We found differences in mutation signatures between males and females across the different populations. To understand better how the cancer starts, we will try to learn how the signatures are generated.”
The long-term goal is to “develop treatments tailored to individuals, and this work will be a stepping stone toward that goal—but it may be a long way from that ultimate goal,” he says. “Our results could eventually lead to strategies for prevention of the disease.”
The research applies to both men and women, Wheeler adds. “The incidence of liver cancer is three to five times higher in men than women. Understanding the reason for this difference will help both men and women in leading to treatments for the disease.”
The incidence of liver cancer is lower in the United States than in other countries worldwide, he says; however, it is increasing in frequency nationwide, whereas the incidence of other leading U.S. cancers—such as lung, colon and breast cancer—is decreasing.
“Unlike the leading U.S. cancers, we do not have screening methods that can give early warning of the disease, so it is a deadly cancer,” Wheeler notes. “Baylor College of Medicine has a nationally recognized liver transplant center headed by Dr. John Goss, and they encounter many patients with hepatocellular carcinoma. So the disease is very important, and we had an opportunity to study it.”
In Asia, where liver cancer is “one of the most prevalent, Asians have large national programs to study the disease,” Wheeler says. “By teaming up with the Japanese, we were able to increase the statistical power of our study to make new discoveries, and we were able to do a racial comparison.”
The study design “did not permit us to tease apart the genetic and environmental factors,” Wheeler admits. “We hope to do that in the context of a 2,000-patient study, where we will be able to compare patients of Asian descent raised in the West to those raised in their native country.”

Baylor hopes to organize a worldwide liver cancer study “pooling together patients from France, Korea, Japan and the U.S. to gain a set of 2,000 patients.”
In the current study, data from 503 liver cancer genomes derived from different populations identified 30 candidates as genes that drive the cancer and 11 cancer pathways. In addition, the collaboration of two large-scale genome projects analyzed the changes found in 608 liver cancer cases, and in doing so, identified the mutational pattern associated in the disease in Japanese men, Wheeler said.
The study found more extensive mutation in the mTOR pathways than had been realized before, suggesting that drugs that inhibit that pathway might be useful. The mTOR pathway is an intracellular pathway important in programmed cell death and thus, cancer.
One such drug is everolimus, an anticancer drug used in treating kidney as well as some types of pancreatic, breast and brain cancers that might also be effective in liver cancer, Wheeler suggests.
The study’s first authors include Yasushi Totoki of the Division of Cancer Genomics at NCCRI, Kenji Tatsuno of the Genome Science Division of the Research Center for Advanced Science and Technology at the University of Tokyo and Kyle R. Covington of the BCM-HGSC. Research also took place at the NCC and the Nihon University School of Medicine in Tokyo.
The corresponding authors include Wheeler, Dr. Hiroyuki Aburatani of the Genome Science Division of the Research Center for Advanced Science and Technology at University of Tokyo and Dr. Tatsuhiro Shibata of the Division of Cancer Genomics at NCCRI.

Immune-related gene may predispose to HPV-related cancer
HOUSTON—An international coalition of cancer specialists led by a researcher now at Baylor College of Medicine has identified an immune-related gene called transforming growth factor beta receptor 1 (TGFBR1) that appears to play an important role in determining whether a person develops a cancer related to human papilloma virus (HPV). HPV is, in particular, associated with anal cancer and cancers of the cervix and the head and neck.
Until recently, head and neck cancer has been found primarily in smokers, but there has been a rise in HPV-associated head and neck cancer in nonsmokers. The head and neck cancer most associated with HPV is oropharyngeal cancer, involving the tonsils and base of the tongue.
HPV is also one of the most common sexually transmitted diseases, with certain strains known to cause head and neck and/or cervical cancer.
“The real mystery is that in Western countries, pretty much everyone is exposed to HPV but only a small number of people get HPV-related cancers,” said Dr. Andrew Sikora, vice chair for research in the Department of Otolaryngology Head and Neck Surgery at Baylor. “We are trying to figure out what makes the people who actually get the cancer different from those who don’t, given that so many people are exposed.”
Using data collected as part of a genome-wide association study of head and neck cancer performed by the INHANCE consortium, the researchers were able to associate alterations in a number of immune-related genes with oropharyngeal cancer. One of these genes, TGFBR1, was found to be deregulated in patients with both oropharyngeal and cervical cancer.
“The fact that we were able to independently replicate our findings in two different HPV-related cancers is exciting, because it suggests that we have found something that is critical to the biology of how HPV causes cancer,” said Sikora, who is also co-director of the head and neck cancer program in the National Cancer Institute-designated Dan L. Duncan Cancer Center at Baylor.
“We hope to learn more about this gene and how it affects cancer,” Sikora added. “In the future, we hope to develop a tool to identify who is more susceptible to HPV-related cancers.”
Sikora conducted the study while on faculty at the Icahn School of Medicine at Mount Sinai in New York prior to joining the Baylor faculty in July 2014.

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