Posted: March 14, 2017
View the TCGA cholangiocarcinoma findings in Cell Reports, here.
TCGA Investigators Improve Understanding of the Molecular Drivers of Cholangiocarcinoma
Researchers with The Cancer Genome Atlas (TCGA) Research Network performed an integrated molecular analysis of 38 cholangiocarcinoma tumors, rare cancers that originate in the body’s bile ducts. Cholangiocarcinoma is associated with a poor prognosis because it is often diagnosed at an advanced stage and does not respond well to conventional chemotherapies. The new study, published in Cell Reports on March 14, 2017, reveals features of the disease that could lead to new therapeutic opportunities.
Specifically, the analysis found several alterations in tumor suppressor genes and oncogenes that were consistent with previous studies, including changes that limit the expression of CDKN2, BAP1, and ARID1 genes, and that promote the excessive expression of FGFR2 and IDH1/2 genes. To better understand the role of these alterations, the researchers grouped cholangiocarcinoma tumors according to their mRNA transcripts, their patterns of chemical marks called DNA methylation, and by their number of copies of chromosomes. This technique divided cholangiocarcinoma into four distinct subtypes. One subtype was characterized by alterations in IDH, which were associated with low expression of genes that encode proteins that change the architecture of DNA, called chromatin modifiers, and with high expression of genes involved in metabolism of the mitochondria. In addition, silencing of ARID1A, a gene that codes for a chromatin modifier, was a common feature of the IDH-associated tumors, suggesting a potential biological mechanism of IDH-driven tumor development. Another subtype was characterized by BAP1 mutations and FGFR2 gene fusions. The authors also compared cholangiocarcinoma to TCGA data on liver carcinoma, and found support for the hypothesis that cholangiocarcinoma is part of a continuous spectrum with liver tumors. They observed that a small subset of the liver carcinomas contained IDH mutations or FGFR fusions and mapped with cholangiocarcinoma on a genomic level. Together, these findings reveal novel biological characteristics and subtypes of cholangiocarcinoma that warrant further investigation to tailor treatments for patients. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.