Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.

Abstract

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

• Authors: Yuchen Jiao, Timothy M Pawlik, Robert A Anders, Florin M Selaru, Mirte M Streppel, Donald J Lucas, Noushin Niknafs, Violeta Beleva Guthrie, Anirban Maitra, Pedram Argani, G Johan A Offerhaus, Juan Carlos Roa, Lewis R Roberts, Gregory J Gores, Irinel Popescu, Sorin T Alexandrescu, Simona Dima, Matteo Fassan, Michele Simbolo, Andrea Mafficini, Paola Capelli, Rita T Lawlor, Andrea Ruzzenente, Alfredo Guglielmi, Giampaolo Tortora, Filippo de Braud, Aldo Scarpa, William Jarnagin, David Klimstra, Rachel Karchin, Victor E Velculescu, Ralph H Hruban, Bert Vogelstein, Kenneth W Kinzler, Nickolas Papadopoulos, Laura D Wood
• Journal: Nature genetics (Nat Genet) Vol. 45 Issue 12 Pg. 1470-1473 (Dec 2013) ISSN: 1546-1718 [Electronic] United States
• PMID: 24185509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ARID1A protein, human
• BAP1 protein, human
• DNA-Binding Proteins
• Nuclear Proteins
• PBRM1 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• Ubiquitin Thiolesterase

Topics

• Bile Duct Neoplasms
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma (epidemiology, genetics)
• Cohort Studies
• DNA-Binding Proteins
• Exome (genetics)
• Female
• Gene Frequency
• Humans
• Liver Neoplasms (epidemiology, genetics)
• Male
• Mutation, Missense
• Nuclear Proteins (genetics)
• Sequence Analysis, DNA
• Survival Analysis
• Transcription Factors (genetics)
• Tumor Suppressor Proteins (genetics)
• Ubiquitin Thiolesterase (genetics)