Clinicopathologic and genomic characteristics of biliary tract carcinomas with TERT promoter mutations among East Asian population

Telomerase reverse transcriptase gene promoter (TERT) mutations are biomarkers that predict survival and responses to immune checkpoint inhibitors in various malignancies. However, their prevalence and clinicopathologic characteristics in biliary tract carcinomas are largely unknown. We performed a comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 485 carcinomas, including intrahepatic (n = 220), perihilar (n = 54), distal biliary tract (n = 110), and gallbladder (n = 101) cancers, using next-generation sequencing. TERT mutations were observed in 50 out of 485 biliary tract cancers (10.3 %) consisting of 39 C228T (78.0 %) and 11 C250T (22.0 %) variants. Among the different anatomic locations, TERT mutations were most frequent in the gallbladder (20.8 %), followed by perihilar (9.3 %), intrahepatic (7.7 %), and distal bile ducts (6.4 %) (p < 0.01). Genetically, TERT mutations were significantly associated with TP53 mutations (p = 0.04), ERBB2 amplification (p < 0.01), and high tumor mutational burdens (TMB) (p < 0.01); moreover, they were negatively correlated with KRAS (p < 0.01), SMAD4 (p = 0.01), and PBRM1 mutations (p = 0.01). In addition, TERT mutations were associated with a poor progression-free survival (PFS, p = 0.01). Specifically, in cases of intrahepatic cholangiocarcinoma, TERT mutations were more frequent in patients with cirrhosis (p = 0.01), hepatitis B virus infection (p = 0.04), and advanced disease stages (p < 0.01). In gallbladder carcinoma, TERT mutations were also associated with poor PFS. In conclusion, TERT mutations in biliary tract carcinomas had unique clinicopathologic and genetic characteristics. Despite its poor PFS, the concomitant presence of ERBB2 amplification and a high TMB indicated a potential for targeted therapy and immunotherapy in this specific subtype.