High incidence of intrahepatic cholangiocarcinoma in end-stage renal disease patients in Taiwan: analysis of a nationwide database with molecular insight of aristolochic acid exposure.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. Its association with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is unclear. Using Taiwan's National Health Insurance Research Database (NHIRD), we analyzed the relationship between iCCA and CKD/ESRD. Molecular alterations were explored through whole-exome sequencing (WES) and Archer FusionPlex in 24 surgical specimens from 22 CKD/ESRD patients. Aristolochic acid (AA)-related DNA adducts were quantified using liquid chromatography/mass spectrometry. NHIRD showed iCCA incidence was 15.35, 26.77, and 34.14 per 100,000 person-years in the general population, CKD, and ESRD patients, respectively. ESRD patients under 65 years had the highest iCCA incidence rate ratio (7.37, P < 0.0001). CKD/ESRD was an independent risk factor (adjusted OR 1.57, P < 0.0001). WES revealed recurrent TP53 (33%), LRP1B (21%), BAP1 (21%) mutations, CDKN2A/B deletion (25%), and FGFR3::TACC3 or SLMAP::ROS1 fusions in single cases. COSMIC SBS22a-associated mutations occurred in 15 cases (68%), more frequent in ESRD-associated tumors (P = 0.05). AA-related DNA adducts were detected in 9 cases (41%), predominantly in ESRD patients (89%). The correlation between SBS22a mutations and dA-AL-I burdens was weak, and canonical T>A transversions were rare in driver mutations. In conclusion, a subset of CKD-/ESRD-associated iCCAs in Taiwan shows molecular and chemical evidence of AA exposure. However, the modest correlation between AA adducts and SBS22a signatures and the paucity of T>A transversions in driver genes suggests that AA acts as a contributory rather than causal factor, possibly synergizing with aging and liver disease-related mutagenic processes.