The largest ever study of the genomes of liver tumors identified a mutation signature that contributes more to cases of the disease in Japanese males that in men of European ancestry, said an international consortium of researchers 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, professor in the Baylor College of Medicine Human Genome Sequencing Center and a corresponding author of the report. Researchers from the University of Tokyo, The National Cancer Center Research Institute and the National Cancer Center Hospital in Tokyo, Japan, were also colleagues on this work.
“Patients are subject to different environmental factors or they are genetically different,” said Wheeler, also a member of the NCI-designated Dan L. Duncan Cancer Center at Baylor. The profiles of the tumors were not associated with hepatitis B, hepatitis C or cirrhosis, which are known environmental factors associated with hepatocellular carcinoma (liver) cancers.
“Liver cancer occurs in males at two to five times the frequency of females,” he said.
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, said Wheeler.
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. One such drug is everolimus, an anti-cancer drug used in treating kidney as well as some types of pancreatic, breast and brain cancers, might also be effective in liver cancer, said Wheeler. (The mTOR pathway is an intracellular pathway important in programmed cell death and, thus, cancer.)’
The study’s first authors include Yasushi Totoki of the Division of Cancer Genomics at the National Cancer Center Research Institute in Tokyo, 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 Human Genome Sequencing Center at Baylor College of Medicine. Research also took place at the National Cancer Center Hospital in Tokyo and Nihon University School of Medicine in Tokyo.
Corresponding authors include Wheeler, Dr. Hiroyuki Aburatani of the Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo and Dr. Tatsuhiro Shibata of the Division of Cancer Genomics, National Cancer Center Research Institute in Tokyo, Japan.
Funding came from Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan for the third-term Comprehensive 10-Year Strategy for Cancer Control, grants from the U.S. National Human Genome Research Institute ( 5U54HG003273) and National Cancer Institute (HHSN261201000053C), the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation (NIBIO) and the National Cancer Center Research and Development Funds (23-A-8). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The supercomputing resource SHIROKANE was provided by the Human Genome Center at the University of Tokyo.