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<p>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&#xa0;years had the highest iCCA incidence rate ratio (7.37, <i>P</i> &lt; 0.0001). CKD/ESRD was an independent risk factor (adjusted OR 1.57, <i>P</i> &lt; 0.0001). WES revealed recurrent <i>TP53</i> (33%), <i>LRP1B</i> (21%), <i>BAP1</i> (21%) mutations, <i>CDKN2A/B</i> deletion (25%), and <i>FGFR3::TACC3</i> or <i>SLMAP::ROS1</i> fusions in single cases. COSMIC SBS22a–associated mutations occurred in 15 cases (68%), more frequent in ESRD-associated tumors (<i>P</i> = 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&gt;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&gt;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. </p>

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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

  • 期刊论文

  • 发表日期：

    2026年1月17日

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  • Shih-Chiang Huang,
  • Ian Yi-Feng Chang,
  • Li-Ching Wu,
  • Meng-Yun Hung,
  • Huei-Chieh Chuang,
  • Chung-Han Ho,
  • Tse-Ching Chen,
  • Chia-Chun Chiu,
  • Chien-Cheng Chen,
  • Kuang-Hua Chen,
  • Ta-Sen Yeh,
  • Jun-Te Hsu,
  • Kwai-Fong Ng,
  • Chien-Feng Li

摘要

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.