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.

Mutational landscape of intrahepatic cholangiocarcinoma

“…TP53 is mutated in 39 (38.2%) of this cohort of ICC patients, a frequency within the range of frequencies reported in some previous studies targeting TP53 in ICCs, but is substantially higher than many frequencies reported previously. For example, this frequency is much higher than that (6%) reported in the cohort of 32 ICC patients treated at various hospitals in the United States of America 24 , that (9.8%) reported in the cohort of 41 ICC patients from Singapore 23 and that (8.9%) reported in the cohort of 45 ICC patients from Romania 23 . These patients (who are from Singapore and Romania) and patients studied here do not have liver fluke infection, suggesting that factors other than liver fluke infection contributed to the differences in mutation prevalence.…”

“…This study suggests a unique role of mutations in PTEN in the tumorigenesis of ICC. Similarly, although mutations in ARID1A have not been found in a previous study on a cohort of 54 ICC patients with liver fluke infection, mutations in this gene have been found in two recent studies with larger sample sizes 23,24 , suggesting the importance of obtaining larger cohorts of ICC patients in mutation discovery studies. They have also been reported in multiple HCC cancer genomics [12][13][14] .…”

“…Second, these studies revealed striking uniqueness in mutation prevalence of key genes between different cohorts of ICC patients, suggesting important contribution of genetic differences of the ICC patients and different risk factors to the mutational landscape. For example, the three frequently mutated genes BAP1, ARID1A and PBRM1 found in a more recent project 24 were completely missing in the earlier study 22 . In addition, ICC patients with liver fluke infection in Thailand showed dramatic differences in mutated genes from those without infection in Singapore 23 .…”

“…A recent project searched for genome-wide somatic mutations in a small cohort of eight patients with cholangiocarcinoma associated with liver fluke infection 22 . Very recently, two sequencing projects reported novel mutations in relatively larger cohorts of ICC patients 23,24 , revealing two striking features of ICC. First, these studies revealed high genetic heterogeneity of ICC.…”

“…First, these studies revealed high genetic heterogeneity of ICC. For example, in a cohort of 32 ICC patients in the discovery screen and an additional 32 ICC patients in the prevalence screen, no single gene was mutated in 425% of the ICC tumours screened 24 . Second, these studies revealed striking uniqueness in mutation prevalence of key genes between different cohorts of ICC patients, suggesting important contribution of genetic differences of the ICC patients and different risk factors to the mutational landscape.…”