Teasing Out The Subtypes Of Bile Duct Cancer

Patients with bile duct cancer are not all alike, according to a study that analyzed the whole genomes of almost 500 patients from ten countries.

AsianScientist (Aug. 10, 2017) – In a study published in the journal Cancer Discovery, researchers have used whole genome sequencing to identify four subtypes of bile duct cancer which may respond differently to treatment.

Bile duct cancer, also known as cholangiocarcinoma (CCA), is a rare but highly lethal form of cancer. Patients diagnosed with CCA have a dismal prognosis as the disease is considered incurable. Surgery is the only proven intervention for this disease and clinical trials evaluating targeted therapies in unselected CCA populations have shown minimal benefits.

The present study, led by the National Cancer Centre Singapore (NCCS), Duke-NUS and Duke University Medical Schools, the Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore (GIS) and NUS’ Cancer Science Institute of Singapore, is a major international effort as part of the International Cancer Genome Consortium (ICGC).

This is the first time Singapore is taking the lead on such a large-scale, multinational cancer genomics project. Besides Singapore, the work was also co-led by investigators from Thailand’s Khon Kaen University, Japan’s National Cancer Center, and the US.

The study analyzed genomic and epigenomic molecular data of 489 CCA cases from ten countries, including Singapore, Thailand and Japan, including both liver fluke-induced (food-borne parasites) CCA and non-liver fluke related CCA. Through the analysis of different types of molecular data, the team identified four subtypes, each revealing distinct molecular behaviors with potential therapeutic opportunities.

The team observed that one subtype, which comprised mostly non-liver fluke related tumors, could potentially respond to immunotherapy. Other subtypes were potentially amenable to targeted therapies currently available or in development for other cancers.

“Our study showed that a third of CCA patients may be potentially treated by targeted therapies, including immunotherapy, HER2 inhibitors, or FGFR inhibitors,” said Professor Teh Bin Tean, co-Principal Investigator of the study and Deputy Director (Research) at NCCS.

The results also demonstrate that development of CCA involves interactions between genetics, epigenetics and environmental carcinogens, which generate distinct molecular subtypes of CCA in different countries.

“Such distinct pathways to cancer illustrates the roles of different risk factors leading to CCA, and highlights the need to identify and manage different risk factors in different regions of the world,” said Professor Patrick Tan, co-Principal Investigator of the study and Professor of the Cancer & Stem Cell Biology Program at Duke-NUS Medical School.

The study was enabled by state-of-the-art sequencing techniques, allowing the investigation of the entire genomes of tumors rather than just genes which have been traditionally studied in cancer genetics.

“Our study showed that changes in the other 98 percent of the genome, including structural variations and noncoding mutations, also contribute to CCA tumorigenesis. The whole-genome sequences of CCAs that we generated in this study is the largest among CCA studies to date, and represent a valuable community resource for further research in this field,” said Professor Steve Rozen, co-Principal Investigator of the study and Director of the Centre for Computational Biology at Duke-NUS Medical School.

The study also showed that leveraging molecular profiles to classify CCA may be useful in the clinical setting, compared to the current approach which uses the anatomical location of the tumor. While CCAs in different anatomical sites do not differ in prognosis or treatment options, the subtypes discovered by the researchers showed significant differences in prognosis and treatment options.

The article can be found at: Jusakul et al. (2017) Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.


Source: A*STAR; Photo: Shutterstock.
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