Integrative genomic analyses of European intrahepatic cholangiocarcinoma: new ROS1 fusion gene and PBX1 as prognostic marker

ABSTRACT: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis due to limited therapeutic options. Intrahepatic CCA (iCCA) is particularly rising worldwide and its molecular basis is just emerging. Environmental factors contribute to regional differences in mutation spectrum with European iCCA patients being underrepresented in systematic genomic and transcriptomic studies. Here we describe an integrated whole exome sequencing and transcriptomic study of 37 iCCAs of German patients. We observed as most frequently mutated genes ARID1A (14%) and IDH1, BAP1, TP53, KRAS, and ATM each in 8% of patients. We identified FGFR2::BICC1 fusions in two tumors and FGFR2::KCTD1 and TMEM106B::ROS1 as new fusions and therapeutic targets for iCCA. Using a data integration framework, we identified PBX1 as a new central regulatory gene for iCCA. We performed an extended screen by targeted sequencing of additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes and we found PBX1 to show copy gain in 20% of tumors. Considering other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs. Analyzing an additional European cohort of iCCA, we found PBX1 protein expression to be a marker for poor prognosis. Overall, our findings add insight into key molecular alterations of iCCA, reveal new targetable fusion genes, and suggest PBX1 as a new modulator of the disease.

PROVIDER: EGAS00001007525 | EGA |

REPOSITORIES: EGA