Exome Sequencing Identifies Frequent Inactivating Mutations in Intrahepatic Cholangiocarcinomas

A key role of dysregulated chromatin remodeling

Exome sequencing of 32 intrahepatic cholangiocarcinomas has revealed recurrent inactivating mutations in several genes involved in chromatin remodelling that were previously unknown in this type of cancer. The study also identified frequent mutations at previously reported hotspots in the genes encoding metabolic enzymes. The findings are published as a research letter in the Nature Genetics on 3 November, 2013 by Yuchen Jiao of the Ludwig Center, Johns Hopkins University, Baltimore, USA and international study colleagues. The corresponding authors are Aldo Scarpa, Kenneth Kinzler, Nickolas Papadopoulos and Laura Wood.

Through exomic sequencing of intrahepatic cholangiocarcinomas, the study team discovered frequent inactivating mutations in multiple chromatin-remodeling genes, including BAP1, ARID1A and PBRM1). Mutation in one of these genes occurred in almost half of the carcinomas sequenced.

Dysfunctional metabolism has also been implicated in this cancer type with the identification of frequent mutations in IDH1 and IDH2, which encode isocitrate dehydrogenase. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. The authors concluded that these discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

As competing financial interests, the authors reported under agreements between Johns Hopkins University, Genzyme, Myriad Genetics, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, Victor Velculescu, Nickolas Papadopoulos, Bert Vogelstein, Kenneth Kinzler and Ralph Hruban are entitled to a share of the royalties received by Johns Hopkins University on sales of products related to genes and technologies described in this manuscript. Victor Velculescu, Nickolas Papadopoulos, Bert Vogelstein and Kenneth Kinzler are cofounders of Inostics and Personal Genome Diagnostics, are members of their scientific advisory boards and own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy. Laura Wood is a paid consultant for Personal Genome Diagnostics. The contribution of Donald Lucas to this manuscript represents his own views and not the official policy of the USA Navy, USA Department of Defense or USA government.


Jiao Y, Pawlik TM, Anders RA et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nature Genet 2013; 45(12):1470-3. doi: 10.1038/ng.2813. Epub 2013 Nov 3.