Genomic spectra of biliary tract cancer

Abstract

The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

“…In addition to mutations, K‐Ras gene amplifications occur in a subset of cholangiocarcinomas (Nakamura et al ., 2015). We therefore determined the K‐Ras amplification status of each cell line by qPCR, identifying three amplified lines (SNU‐245, SNU‐1196 and NOZ) (Fig.…”

“…While K‐Ras mutations and amplifications do occur in primary BTC, the collective frequency of these events in the cell line panel (45%) is significantly greater than that observed in primary cancers (18%) (Nakamura et al ., 2015), suggesting that tumours harbouring these genetic alterations may be more amenable to cell line generation.…”

“…Genetic alterations that constitutively activate this pathway also occur, although at low frequency. These include activating mutations in PIK3CA (4–7%) (Nakamura et al ., 2015; Riener et al ., 2008), inactivating mutations in PIK3R1 (4%), TSC1 (3%), TSC2 (1%) and amplifications in AKT3 (3%) (Nakamura et al ., 2015). Finally, 5–30% of BTCs harbour mutations, amplifications and fusions in receptor tyrosine kinases of the Erb and FGFR families, and c‐MET (Hezel et al ., 2010; Li et al ., 2014; Nakamura et al ., 2015; Voss et al ., 2013), which can all activate signalling through the PI3K/AKT/mTOR pathway.…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…In general, HCV-related diseases show an increased associ ation with CCA in Europe and other Western countries; the association with HBV is more statistically significant where the prevalence of HBV infection is high, including Asian countries 27,28 . Occult HBV infection is an emerging risk factor for iCCA 29 . The increased incidence of iCCA, registered at the end of the past century, has been linked with the burden of HCV infection 29,30 .…”

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

“…Recent next-generation sequencing technology has enabled comprehensive mutational profiling of CC and has shown that the mutational spectrum differs according to anatomical subtype and underlying etiology (3,4). In the embryonic stage, the extrahepatic bile duct (EHBD) develops from the embryonic hepatic diverticulum, whereas the intrahepatic bile duct (IHBD) originates within the liver from the ductal plate (5).…”