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Exome Sequencing IDs Mutations in Liver Fluke-Associated Bile Duct Cancer

NEW YORK (GenomeWeb News) – A form of bile duct cancer associated with liver fluke infection appears to share some mutation patterns with a pancreatic cancer called pancreatic ductal adenocarcinoma, a new study suggests.

An international team led by investigators in Singapore and Thailand did whole-exome sequencing on tumor-normal samples from eight individuals with the bile duct cancer cholangiocarcinoma, or CCA, that were related to infection by the Southeast Asian liver fluke Opisthorchis viverrini.

As they reported online yesterday in Nature Genetics, the researchers found somatic mutations in nearly 200 genes in the tumor exomes, including known cancer genes such as TP53 and KRAS.

Through follow-up analyses involving dozens more individuals with CCA, meanwhile, they were able to start teasing apart the genes and pathways that are most often affected in liver fluke-related forms of the cancer. Some of the mutations found were specific to CCA tumors. But other genetic features found in the bile duct cancers resembled those previously reported for pancreatic ductal adenocarcinoma, or PDAC, which appears more similar to CCA than another liver cancer, hepatocellular carcinoma.

"Taken together, these results suggest that, at the molecular level, CCA and PDAC have more in common in their mutational spectra, pointing to common biological pathways shared by CCA and PDAC tumorigenesis," co-first authors Choon Kiat Ong and Chutima Subimerb, who are affiliated with Singapore's National Cancer Centre and Duke-National University of Singapore, and colleagues wrote.

Although CCA typically represents less than a quarter of the liver cancer cases diagnosed around the world, the researchers explained, it is inordinately common in parts of Southeast Asia, including regions of Thailand, Cambodia, and Laos where the liver fluke O. viverrini is also found.

For the current study, researchers decided to focus on O. viverrini infection-related forms of the disease, starting with CCA tumor and matched normal samples from eight individuals who had been treated for O. viverrini-related CCA at Thailand's Srinagarind Hospital.

Coding sequences captured from the tumor-normal samples using Agilent's SureSelect Enrichment System were sequenced to 80 times coverage, on average, by Illumina GAIIx or HiSeq 2000 paired-end sequencing.

When they analyzed these exomes sequences, the researchers found between 19 and 34 mutations per tumor, with each containing an average of 26 mutations.

From the 206 Sanger-verified somatic mutations detected in 187 genes in the tumor exomes, they then picked out 13 that were mutated in at least two of the CCA tumor exomes and used targeted Sanger sequencing to test them in samples from another 46 individuals with CCA treated at the same Thai hospital. Two other genes — CDKN2A and PTEN — were tested in that group as well, the study's authors noted, to get a sense of how CCA-associated mutations compared with those previously reported for the liver cancer HCC and the pancreatic cancer PDAC.

Across all 54 tumors tested by exome or targeted sequencing, TP53 was the most frequently mutated gene, carrying non-synonymous changes in 44 percent of the CCA cases.

Other recurrently mutated genes included KRAS and SMAD4, which were each altered in 16.7 percent of the CCA cases, MLL3 (non-synonymously mutated in almost 15 percent of CCA cases), and the ROBO2, RNF3, and GNAS genes, which were each mutated just over 9 percent of the time. Several other genes were mutated at between 3.7 percent to 5.6 percent frequency in the tumors.

When the team took gene function and the predicted consequences of mutations into account, it found evidence that O. viverrini-related CCA often involves mutations that are expected to lead to genome instability, enhanced signaling through G-protein pathways, and altered histone modification.

The researchers also found genetic changes in the O. viverrini-related CCA tumors that were reminiscent of those reported in PDAC, noting that "CCA tumors seem to share more mutational characteristics with PDAC than with HCC, both in terms of individual validated genes and the entire mutation spectrum."

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