Accumulating Genetic Mutations from Primary to Secondary Biliary Tract Cancers - Analysis of Four Patients With Metachronous Biliary Tract Cancer Using Comprehensive Genomic Profiling

Sep 23, 2026

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Metachronous biliary tract cancer (BTC) occurs rarely after curative resection of primary BTC, yet its genetic drivers and pathogenesis remain insufficiently characterized. Four patients treated at Nagoya University Hospital (2010–2024) were analyzed with next-generation sequencing using matched gene panels on primary and secondary tumors. A 24-month median interval was observed, with genetic alterations detected in all paired lesions. Mutation burden increased in metachronous tumors, and CDKN2A and SMAD4 were the most frequently altered. Shared mutations across all cases suggest a common clonal origin.

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Abstract

Background/Aim

Patients and Methods

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Introduction

Patients and Methods

doi: 10.21873/cgp.20505 Accumulating Genetic Mutations from Primary to Secondary Biliary Tract Cancers: Analysis of Four Patients With Metachronous Biliary Tract Cancer Using Comprehensive Genomic Profiling TOSHIO KOKURYO, YOSHIO KOIKE, JUNPEI YAMAGUCHI, MASAKI SUNAGAWA, TAISUKE BABA, NOBUYUKI WATANABE, SHUNSUKE ONOE, TAKASHI MIZUNO and TOMOKI EBATA Division of Surgical Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan Abstract Background/Aim: Metachronous biliary tract cancer (BTC) is a rare occurrence after curative resection of primary BTC. The genetic alterations and pathogenesis associated with metachronous BTC remain poorly understood. Patients and Methods: We analyzed four patients with metachronous BTC who underwent resection at the Nagoya University Hospital between 2010 and 2024. Gene panel examination was performed on both primary and secondary tumors using next‑generation sequencing. Results: The median interval between resection of the primary tumor and diagnosis of metachronous BTC was 24 months. Genetic alterations were observed in all paired primary and metachronous carcinomas. The number of genetic mutations was higher in metachronous lesions than in primary lesions. CDKN2A and SMAD4 were the most frequently mutated genes in all metachronous lesions. Common genetic mutations between primary and metachronous lesions were confirmed in all four cases, suggesting a common clonal origin. Conclusion: This study demonstrated that characteristic genetic alterations and their accumulation play important roles in metachronous BTC. This suggests that the increasing burden of gene mutations may play a crucial role in the carcinogenesis of metachronous BTC. Further investigation is required to validate these findings and elucidate the underlying molecular mechanisms. Keywords: Metachronous biliary tract cancer, genetic mutation accumulation, comprehensive genomic profiling, next‑generation sequencing, field cancerization, clonal origin, genetic predisposition, CDKN2A, SMAD4, carcinogenesis. ✉ Toshio Kokuryo, Division of Surgical Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai‑cho, Showa‑ku, Nagoya 466‑ 8550, Japan. Tel: +81 527442222, Fax: +81 527442230, e‑[mail: kokuryo.toshio.f8@f.mail.nagoya](mail: kokuryo.toshio.f8@f.mail.nagoya)‑[u.ac.jp](u.ac.jp) Received October 15, 2024 | Revised November 28, 2024 | Accepted December 3, 2024 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. ©2025 The Author(s) . Anticancer Research is published by the International Institute of Anticancer Research. Introduction Biliary tract cancer (BTC) is a malignant neoplasmarising from the epithelial cells at any site in the biliary tree, including the intrahepatic and extrahepatic bile ducts, and gallbladder (1) . Clinically, most patients with BTC have advanced disease at initial presentation, highly associated with poor prognosis (2) . Surgical resection is the only potentially curative treatment; however, recurrence is common even after curative resection, with an incidence ranging from 57% to 67%(3, 4), thereby resulting in unsatisfactory survival rates of less than 30%(5, 6) . Although tumor relapse after surgery generally includes distant and locoregional metastases, a rare mode of tumor relapse has been reported and referred to as metachronous BTC, which is defined as a new BTC development after the R0 resection of the initial BTC (7) . With a prevalence approximately 7%, this rare event masks the pathologic nature of the secondary BTC: genuine new secondary lesions versus metastatic foci from the primary disease (8). However, its tumorigenesis is clinically important for deciding on the therapeutic approach; up‑front definitive surgery should be considered for new secondary lesions whereas systemic chemotherapy is t

FAQs

What is metachronous biliary tract cancer in this study?

Metachronous BTC refers to the development of a new BTC after R0 resection of the initial primary BTC. The study focuses on genetic differences between primary and subsequent lesions.

How were genetic alterations measured?

Matched primary and metachronous tumors from four patients were assessed using gene panel examination with next-generation sequencing.

Which genes were most frequently mutated in metachronous lesions?

CDKN2A and SMAD4 were reported as the most frequently mutated genes across all metachronous lesions.

Sep 23, 2026

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