A common genetic variant in the TERT gene may have two opposing effects in cholangiocarcinoma: reducing the risk of developing the disease while being associated with worse outcomes after cancer develops.
Dr. Georg Lurje and colleagues from Charité – Universitätsmedizin Berlin reported these findings in eGastroenterology. The study combined large-scale population genetics, clinical outcome analysis, tumor transcriptomics, and serum proteomics to investigate how inherited genetic variation influences both cancer susceptibility and prognosis.
Cholangiocarcinoma is a rare but highly aggressive liver cancer with limited options for early risk prediction and frequent recurrence after surgery. The researchers aimed to identify inherited variants associated with intrahepatic cholangiocarcinoma (iCCA) and determine whether these variants also affect patient outcomes.
Large-scale genetic analysis identifies TERT variant linked to iCCA risk
The researchers first analyzed 26 candidate single-nucleotide polymorphisms (SNPs) using genetic and health data from more than 500,000 UK Biobank participants.
Among all tested variants, TERT rs10069690 showed the strongest association with iCCA risk. Individuals carrying the T allele had a lower incidence of iCCA compared with those carrying the C/C genotype (adjusted OR 0.824, 95% CI 0.713–0.951).
TERT encodes the catalytic component of telomerase, an enzyme involved in maintaining chromosome ends and cellular longevity. In addition to its classical role in telomere biology, TERT also regulates pathways involved in cell proliferation, DNA repair, and cancer progression.
The same variant is associated with poorer survival after surgery
To investigate whether the variant also influenced clinical outcomes, the team analyzed 221 patients who underwent surgical resection for intrahepatic or perihilar cholangiocarcinoma at Charité between 2010 and 2020.
Although tumor characteristics were largely comparable between genetic groups, patients carrying the T allele experienced significantly shorter overall survival after surgery. Median overall survival was 21 months among T-allele carriers compared with 31 months among C/C homozygotes.
Multivariable analysis confirmed that the TERT variant remained an independent predictor of poorer overall survival, together with established clinical factors including lymph node invasion and positive surgical margins.
Molecular analyses reveal potential mechanisms
To understand the biological basis of these findings, the researchers analyzed publicly available RNA-sequencing data from 244 resected iCCA tumors.
Higher TERT expression was associated with activation of pathways involved in cell-cycle progression, nuclear division, DNA repair, and RNA processing, suggesting enhanced tumor cell proliferation. Meanwhile, pathways related to cell differentiation, adhesion, and immune function were reduced.
Interestingly, the immune-related pathway most strongly associated with increased TERT expression involved regulatory T cells (Tregs), which are known to contribute to immune suppression within the tumor microenvironment.
Systemic immune differences in healthy genetic carriers
The researchers also examined serum protein profiles from more than 50,000 cancer-free UK Biobank participants.
Compared with individuals carrying the C/C genotype, TERT variant carriers showed differences in proteins involved in immune regulation. These changes suggested altered lymphocyte differentiation and reduced natural killer (NK)-cell-mediated immune activity.
These findings provide possible clues as to why the same genetic variant may have different effects before and after cancer development.
A context-dependent role for TERT in cancer
The authors propose that the TERT rs10069690 variant may influence different stages of cancer development in distinct ways. Before tumor formation, altered telomerase activity may reduce the likelihood of malignant transformation. However, once cancer is established, TERT-related molecular programs may promote tumor growth and immune escape.
The study is exploratory and requires validation in additional populations and functional studies. Nevertheless, the findings identify TERT rs10069690 as a potential biomarker for both cholangiocarcinoma risk assessment and postoperative prognosis, while highlighting TERT as a promising target for future therapeutic research.
See the article:
Lurje I, Pein J, Horn P, et al. TERT rs10069690 variant is linked to reduced cholangiocarcinoma incidence but adverse prognosis in patients undergoing resection. eGastroenterology 2026;4:e100320. doi:10.1136/egastro-2025-100320
About eGastroenterology
eGastroenterology, a BMJ journal partnered with Gut and launched by leading scientists in gastroenterology and hepatology, has been indexed in the Web of Science Core Collection (ESCI), PubMed, DOAJ, Scopus, CAS, ROAD, and many other major international databases within just two years of its launch.
eGastroenterology has recently received its first Journal Impact Factor of 10.5 and now ranks 11/153 in the Web of Science Gastroenterology & Hepatology category.
