Abstract
Background: Cholangiocarcinoma (CCA) is a rare cancer, with limited understanding of genetic and prognostic determinants. We aimed to explore genetic risk factors, assess their prognostic implications and evaluate associated systemic and intratumoral features.
Methods: We screened the UK Biobank to identify single-nucleotide polymorphisms (SNPs) potentially associated with intrahepatic CCA (International Classification of Diseases, 10th Revision (ICD-10) code: C22.1). Candidate SNPs were genotyped in a real-life cohort of 221 patients undergoing liver resection for intrahepatic or perihilar CCA at Charité – Universitätsmedizin Berlin. Intratumoral gene expression and pathway co-expression were examined. Serum proteomic profiles were evaluated in patients with intrahepatic CCA and the overall population.
Results: In exploratory analyses, the telomerase reverse transcriptase (TERT) rs10069690 T allele was associated with a reduced risk of intrahepatic CCA (T allele vs C/C homozygotes: adjusted OR 0.824 (95% CI 0.713 to 0.951), p=0.008). However, T allele carriers undergoing liver resection for CCA had independently shorter overall survival (OS) compared with C/C homozygotes (median OS 21 (17-25) months vs 31 (24-38) months, p=0.034, HR 1.427 (1.023-1.991)). In serum proteomic analyses of the general population, presence of the T allele was associated with differences in immune-related pathways, including signatures consistent with increased lymphocyte differentiation and reduced NK-cell-mediated cytotoxicity. In intrahepatic CCA tumours, higher TERT mRNA expression was positively correlated with gene expression patterns consistent with increased cell cycle activity and regulatory T cell signatures, and negatively associated with pathways of cell differentiation, adhesion and immune effector function.
Conclusions: These exploratory, hypothesis-generating findings suggest that the TERT rs10069690 variant may be associated with intrahepatic CCA risk and clinical outcomes, as well as with immune-related and proliferative pathways. The observed context-dependent associations warrant independent validation and further functional investigation.