Abstract
Biliary tract cancers exhibit distinct mutational and driver gene spectra across anatomic subtypes.
Major finding: Biliary tract cancers exhibit distinct mutational and driver gene spectra across anatomic subtypes.
Clinical relevance: Genetic alterations in potentially actionable targets were identified in nearly 40% of tumors.
Impact: Immune checkpoint inhibitors may be effective in the poor prognosis subgroup of biliary tract cancers.
The global incidence of biliary tract cancers (BTC), which include intrahepatic cholangiocarcinomas (ICC), extrahepatic cholangiocarcinomas (ECC), and gallbladder cancer, is on the rise. However, the differences in the genomic landscape of these anatomic tumor subtypes have not been well characterized, and targeted therapies for BTCs are lacking. To address these issues, Nakamura and colleagues performed whole-exome and transcriptome sequencing of 260 BTCs representing each tumor subtype. This analysis revealed a larger contribution of an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)–driven mutational signature in gallbladder cancer and ECC compared with ICC, which correlated with the total mutation burden. Recurrent alterations were detected in 32 potential driver genes, including KRAS, TP53, and the previously unidentified candidate BTC tumor suppressor ELF3. Genetic alterations in kinase–RAS genes, TP53, cell-cycle genes, TGFβ pathway components, and epigenetic regulators were common in BTCs. Of note, potentially actionable genetic alterations were observed in 38.9% of BTC tumors analyzed, and the spectra of driver gene alterations exhibited an organ-specific pattern among anatomic BTC subtypes. For example, expression of FGFR2 fusion genes was specifically identified in ICC tumors and resulted in ligand-independent activation of FGFR2 signaling, anchorage-independent growth, and tumor formation. In contrast, ECC tumors were characterized by alterations in genes encoding cAMP-dependent protein kinase catalytic subunit α (PKA) pathway proteins, which enhanced the activation of PKA and downstream MAPK signaling. Furthermore, BTCs with the poorest prognosis were enriched for increased expression of immune checkpoint molecules such as programmed death ligand 1, suggesting that these tumors may be responsive to immune checkpoint blockade. These findings provide insight into the genomic landscape of BTC and suggest potential subtype-specific therapeutic strategies.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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