Prognostic significance of germline ARID5B and LEPR polymorphisms in intrahepatic and perihilar cholangiocarcinoma after curative resection

doi:10.4251/wjgo.v18.i7.120469

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Jul 15, 2026; 18(7): 120469
Published online Jul 15, 2026. doi: 10.4251/wjgo.v18.i7.120469

Prognostic significance of germline ARID5B and LEPR polymorphisms in intrahepatic and perihilar cholangiocarcinoma after curative resection

Smiths S Lueong, Jens Siveke, Tom Luedde, Daniel Heise, Florian WR Vondran, Franziska Alexandra Meister, Georg Lurje, Ulf Neumann, Lara Heij, Jan Bednarsch, Tarick M Al-Masri, Dong Liu, Carlos Otto, Guanwu Wang

Guanwu Wang, Dong Liu, Tarick M Al-Masri, Florian WR Vondran, Franziska Alexandra Meister, Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, North Rhine-Westphalia, Germany

Guanwu Wang, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha 410005, Hunan Province, China

Carlos Otto, Daniel Heise, Ulf Neumann, Lara Heij, Jan Bednarsch, Department of Surgery and Transplantation, University Hospital Essen, Essen 45147, North Rhine-Westphalia, Germany

Dong Liu, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

Tarick M Al-Masri, University of Applied Science Aachen, Aachen 52066, North Rhine-Westphalia, Germany

Smiths S Lueong, Jens Siveke, Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), University Hospital Essen, Essen 45147, North Rhine-Westphalia, Germany

Smiths S Lueong, Jens Siveke, German Cancer Consortium (DKTK), Partner Site Essen, A Partnership Between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen 45147, North Rhine-Westphalia, Germany

Tom Luedde, Department of Hepatology and Infectious Diseases, Heinrich Heine University Duesseldorf, Duesseldorf 40225, North Rhine-Westphalia, Germany

Georg Lurje, Department of Surgery and Transplantation, University Hospital Heidelberg, Heidelberg 69120, Baden-Württemberg, Germany

Ulf Neumann, Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht 6229 HX, Limburg Provincie, Netherlands

Lara Heij, Institute of Pathology, University Hospital Essen, Essen 45147, North Rhine-Westphalia, Germany

Author contributions: Wang G, Otto C and Bednarsch J designed the study, developed the software, wrote the original draft; Wang G, Lueong SS, Siveke J, Heij L and Bednarsch J were responsible for developing the methodology; Liu D and Al-Masri TM performed the validation; Wang G, Otto C, Liu D, Al-Masri TM, Neumann U, Heij L and Bednarsch J participated in the formal analysis; Wang G, Otto C, Liu D, Al-Masri TM, Lueong SS, Siveke J, Heise D, Meister FA, Vondran FWR, Lurje G, Neumann U, Heij L and Bednarsch J participated in the investigation; Neumann U and Bednarsch J provided the resources; Liu D and Al-Masri TM curated the data; Liu D, Al-Masri TM, Lueong SS, Siveke J, Luedde T, Heise D, Meister FA, Vondran FWR, Lurje G, Neumann U and Heij L participated in the review and editing; Wang G and Otto C performed the visualization; Bednarsch J and Neumann U supervised the study; Heij L and Bednarsch J administered the project; Wang G, Liu D and Bednarsch J acquired the funding; and all authors have read the manuscript and approved the final version.

Supported by the China Scholarship Council, No. 202108430018 and No. 202208080011.

Institutional review board statement: This study was conducted in accordance with the current version of the Declaration of Helsinki and good clinical practice guidelines (International Conference on Harmonization, Good Clinical Practice). Approval was granted by the institutional review board (Independent Ethics Committee, RWTH University Aachen, Germany, No. EK 252/15, No. EK 206/09).

Informed consent statement: Signed informed consent was obtained from all participants.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Corresponding author: Jan Bednarsch, MD, Doctor, Department of Surgery and Transplantation, University Hospital Essen, Hufelandstrasse 55, Essen 45147, North Rhine-Westphalia, Germany. jan.bednarsch@uk-essen.de

Received: February 28, 2026
Revised: March 19, 2026
Accepted: April 28, 2026
Published online: July 15, 2026
Processing time: 129 Days and 15 Hours

Abstract

BACKGROUND

Cholangiocarcinoma (CCA) is a biologically heterogeneous and aggressive biliary malignancy associated with poor survival outcomes despite surgical resection. Germline genetic variants, including single-nucleotide polymorphisms (SNPs), may modulate tumor behavior and inform postoperative risk stratification.

AIM

To evaluate the prognostic relevance of selected tumor-related SNPs in patients with intrahepatic CCA (iCCA) and perihilar CCA (pCCA).

METHODS

In this single-centre retrospective cohort study, we genotyped eight SNPs in cancer-associated genes (ARID5B, LEPR, TERT, SH2B3, MMEL1, PROM1, HDAC7, RUNX3) in 229 patients (112 iCCA, 117 pCCA) who underwent curative-intent resection between 2009 and 2020.

RESULTS

Associations between SNPs and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Kaplan-Meier analysis, univariate, and multivariate Cox regression models. The rs10740055 AA genotype in ARID5B was associated with significantly shorter RFS [hazard ratio (HR) = 1.87, P = 0.017], CSS (HR = 1.78, P = 0.033) and OS (HR = 1.79, P = 0.021) in iCCA as well as shorter RFS (HR = 1.84, P = 0.031), CSS (HR = 2.18, P = 0.005) and OS (HR = 1.84, P = 0.001) univariate analyses. However, only in iCCA did it retain significance in multivariate analysis alongside other important clinicopathological variables (RFS: HR = 2.41, P = 0.005; CSS: HR = 2.27, P = 0.020 and OS: HR = 4.10, P = 0.001). Further, the LEPR rs1137101 GG genotype was associated with significantly shorter RFS (HR = 1.91, P = 0.010). Germline variants in ARID5B and LEPR were associated with poorer prognosis following resection for CCA, with rs10740055 in ARID5B serving as an independent predictor of survival particularly in iCCA.

CONCLUSION

These findings support the potential utility of incorporating host genetic markers into postoperative prognostic models for CCA. Prospective validation and mechanistic studies are warranted.

Keywords: Cholangiocarcinoma; Single-nucleotide polymorphisms; ARID5B; LEPR; Prognostic biomarker

Core Tip: This study identifies germline ARID5B rs10740055 and LEPR rs1137101 polymorphisms as prognostic biomarkers in patients undergoing curative resection for intrahepatic and perihilar cholangiocarcinoma. In a cohort of 229 patients, the ARID5B rs10740055 AA genotype was consistently associated with significantly worse recurrence-free, cancer-specific, and overall survival, serving as an independent predictor particularly in intrahepatic cholangiocarcinoma. The LEPR rs1137101 GG genotype was additionally associated with shorter recurrence-free survival in intrahepatic tumors. These findings highlight the potential value of incorporating host genetic variants into postoperative risk stratification and personalized management strategies for cholangiocarcinoma.