Canadian Researchers Identify Mutations Linked to Rare Form of Liver Cancer

Canadian cancer researchers working with patients in China have identified mutations linked to the development of intrahepatic cholangiocarcinoma (ICC), a rare, highly fatal form of liver cancer that disproportionately affects individuals of Asian origin.

ICC, also known as intrahepatic bile duct cancer, accounts for approximately 10% of primary liver malignancies worldwide, but while it strikes only about one in 100,000 people annually in North America, it causes 96 cases per 100,000 people annually in Thailand. Prognosis for ICC patients is poor, as early tumors are usually undetectable due to being hidden in bile ducts located deep inside the body. Thus, the disease is diagnosed only after symptoms develop and the disease has advanced. There are no effective therapies for ICC, and the median survival duration after diagnosis is only six to nine months.


Investigators at Simon Fraser University (Burnaby, BC, Canada) sequenced tumor and matching control sample pairs of a large cohort of 103 Chinese ICC patients, which resulted in the identification of an ICC-specific somatic mutational signature that was associated with liver inflammation, fibrosis, and cirrhosis.

They further uncovered 25 significantly mutated genes including eight potential driver genes (TP53, KRAS, IDH1, PTEN, ARID1A, EPPK1, ECE2 and FYN). Three pathways (Ras/phosphatidylinositol-4,5-bisphosphate 3-kinase signaling, p53/cell cycle signaling, and transforming growth factor-beta/Smad signaling)—genes important for epigenetic regulation and oxidative phosphorylation—were found to be affected substantially in ICC.

"Our research is by far the most comprehensive sequencing effort to identify mutations associated with ICC and will be an important resource for scientists working to improve understanding and therapy for the disease," said contributing author Dr. Nansheng Chen, professor of molecular biology and biochemistry at Simon Fraser University. "Some cancer types, including ICC, are uncommon in Canada, which has a relatively small population but a large diversity of ethnic origins. To get insight into the formation of tumors in these rare cancer types, we have to establish international collaborations like ours to gain access to large sample cohorts. Results from this study could help us understand the driver mutations in Chinese Canadians with intrahepatic bile duct cancer. And our work illustrates that this is a real opportunity and sets up a model for working on rare disease conditions."

The study was published in the December 15, 2014, online edition of the journal Nature Communications.

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