LIVER FLUKE GENETIC SEQUENCING AND CHOLANGICARCINOMA

May 10, 2012 — Cholangiocarcinoma accounts for 10% to 25% of all primary liver cancers worldwide, and generally has a very poor prognosis. In certain parts of Southeast Asia, infection with the liver fluke Opisthorchis viverrini is a major public health problem and is associated with the development of cholangiocarcinoma.

In a letter published online May 6 in Nature Genetics, researchers provide some insight into the "mutational landscape" that contributes to the development of O viverrini–related cholangiocarcinoma.

Bin Tean Teh MD, PhD, from the Duke–National University of Singapore (NUS) Graduate Medical School, and colleagues conducted whole-exome sequencing of 8 O viverrini–related tumors and matched normal tissue. They identify somatic mutations in several genes known to be associated with cancer and in 10 genes newly implicated in the mutational landscape of cholangiocarcinoma. Their findings suggest a role for histone modifiers, G protein signaling, and genome stability in the development of this cancer.

This research could lead to better prognostic or diagnostic tools and improved therapies by targeting certain genes. "We identified likely causal mutations in 10 genes not previously linked to cholangiocarcinoma," coauthor Steve Rozen, PhD, also from the Duke–NUS Graduate Medical School, told Medscape Medical News.

"With this new information, researchers will be able to investigate whether mutations in specific genes can predict which treatments will be most beneficial," he said. "Furthermore, one of the genes that we uncovered,GNAS, seems to be acting as an oncogene. Therefore, it is a potential therapeutic target."

Cholangiocarcinoma is uncommon in Western countries; it has an age-standardized incidence rate (ASR) of less than 1.5 per 100,000, the authors note. However, in some areas of Southeast Asia, primarily in regions with highO viverrini infestation, it is highly prevalent. For example, cholangiocarcinoma is the predominant type of liver cancer found in northeastern Thailand, Laos, and Cambodia, with very high ASRs of 94.8 per 100,000 for men and 39.4 per 100,000 for women.

Surgical resection remains the treatment of choice, the authors note, but most cases are inoperable. There is currently no effective therapy for this malignancy, although the combination of chemotherapy plus gemcitabine and cisplatin does marginally improve the length of survival.

After conducting their whole-exome sequencing, Dr. Teh and colleagues identified and validated 206 somatic mutations in 1187 genes using Sanger sequencing. They then selected 15 genes to screen for the prevalence of mutations in another 46 people with cancer.

In addition to genes that are already known to be cancer causing — including TP53 (mutated in 44.4% of cases),KRAS (16.7%), and SMAD4 (16.7%) — somatic mutations were identified in 10 newly implicated genes in 3.7% to 14.8% of cases. Among these new genes are inactivating mutations in MLL3 (in 14.8% of cases), ROBO2(9.3%), RNF43 (9.3%), and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%).

These genes, the authors note, have functions that can be broadly categorized into 3 main biologic classes: deactivation of histone modifiers, activation of G protein signaling, and loss of genome stability. Genetic alterations to GNAS, RNF43, ROBO2, and PEG3 "are unique" to cholangiocarcinoma, indicating that they appear to have a specific role in this disease.

"The mutations identified highlight important biological aspects of cholangiocarcinoma, and further studies are needed to investigate their roles in cholangiocarcinoma," the authors conclude.

The study was supported in part by funding from the Singapore National Medical Research Council, The Singapore Millennium Foundation, The Lee Foundation, the Singapore National Cancer Centre Research Fund, the Duke–NUS Graduate Medical School, the Cancer Science Institute, Singapore, the Research Team Strengthening Grant, the National Genetic Engineering and Biotechnology Center, and the National Science and Technology Development Agency, Thailand. The authors have disclosed no relevant financial relationships.