Novel gene mutations associated with bile duct cancer

January 18, 2012

Investigators at the Massachusetts General Hospital (MGH) Cancer Center have identified a new genetic signature associated with bile duct cancer, a usually deadly tumor for which effective treatment currently is limited. Their report, which has been published online in The Oncologist, finds that growth-enhancing mutations in two related genes may account for nearly a quarter of bile duct tumors arising within the liver, presenting the possibility that drugs targeting this mutation could represent a new strategy to control tumor growth.

"Patients with bile duct cancer have a generally poor prognosis. Most of them are diagnosed with advanced or metastatic disease, so surgical resection is not feasible," says co-senior author Andrew Zhu, MD, PhD, director of Liver Cancer Research at the MGH Cancer Center. "Identifying this new and relatively common mutation in intrahepatic bile duct cancer may have significant implications for the diagnosis, prognosis and therapy of patients whose tumors harbor this mutation."

Cancers of the gallbladder and bile duct are diagnosed in 12,000 patients in the U.S. each year, the authors note; but only 10 percent are discovered early enough to allow successful surgical treatment. Chemotherapy is modestly effective, leading to an average survival time of less than one year.

The MGH Translational Research Laboratory was jointly established by the MGH Department of Pathology and the MGH Cancer Center to screen patient tumor samples for mutations known to drive tumor growth, identifying those that may be treatable with targeted therapies. As part of this project, the MGH team screened samples from 287 patients with gastrointestinal tumors for 130 known cancer-associated mutations and were surprised to find that 3 out of 12 biliary tract cancer tumors had mutations in a gene called IDH1. To confirm this finding, they ran a more detailed screen in additional samples, for a total of 62 bile duct tumors and 25 gallbladder tumors. Mutations in IDH1 were found in 13 percent of all bile duct tumors and in 23 percent of those located within the liver itself. Less commonly, mutations were identified in a similar gene IDH2.

"Mutations in these genes are rare examples of abnormalities that profoundly affect the normal function of a metabolic enzyme," says lead author Darrell Borger, PhD, co-director of the Translational Research Laboratory. "Our co-investigators previously found that, in other types of cancer, mutations in these genes cause overproduction and dramatic accumulation of the metabolite 2-hydroxyglutarate. How this causes tumor development is being actively investigated, and it is now emerging that 2-hydroxyglutarate can disrupt the activity of a family of proteins important in signal transduction and regulation of gene expression."

Although no approved drugs are currently available that target IDH mutations, extensive efforts are underway to develop such drugs, Zhu notes. "Identifying these mutations in bile duct cancer raises many questions, including whether mutational status can distinguish various types of bile duct tumors and help predict prognosis. Also of interest is determining whether high blood levels of 2-hydroxyglutarate could serve as a biomarker for IDH1/2 status, which could provide a minimally invasive way to monitor the effects of new IDH inhibitors that may become available," he says. Zhu is an associate professor, and Borger an instructor in Medicine at Harvard Medical School.
-end-
John Iafrate, MD, PhD, director of the Center for Integrated Diagnostics in MGH Pathology, is corresponding and co-senior author of the Oncologist paper. Additional co-authors are Kenneth Tanabe, MD, Kenneth Fan, Hector Lopez, Marek Ancukiewicz, PhD, Hannah Liebman, Eunice Kwak, MD, PhD, Jeffrey Clark, MD, David Ryan, MD, Vikram Deshpande, MBBS, Dora Dias-Santagata, PhD, and Leif Ellisen, MD, PhD, all of the MGH Cancer Center; Valeria Fantin, PhD, Kimberly Straley and David Schenkein, MD, Agios Pharmaceuticals; and Aram Hezel, MD, University of Rochester.

Massachusetts General Hospital (www.massgeneral.org), founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Massachusetts General Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.