Revealing the Evolutionary Pathway of Cholangiocarcinoma from Onset to Recurrence and Metastasis

Key Genetic Mutations Identified in Precancerous Lesions

Multiple Cell Groups from Primary Tumor Persist in Recurrent Tumors

'Polyclonality' Observed in the Recurrence Process

New research has found that genetic changes in cholangiocarcinoma begin even before the onset of cancer, and that, upon postoperative recurrence, it is not just a single cancer cell but multiple groups of cancer cells that regrow together.

On September 29, Seoul National University Bundang Hospital announced that the research team led by Professor Kim Ji-won from the Department of Hematology and Oncology and Professor Na Hee-young from the Department of Pathology has identified the ‘evolutionary pathway’ that cholangiocarcinoma undergoes, from the precancerous stage to recurrence and metastasis. The study has been published in the international journal ‘npj Precision Oncology’.

Graphic illustrating the evolutionary pathway of cholangiocarcinoma. Seoul National University Bundang Hospital

Cholangiocarcinoma is a cancer that develops in the pathways through which bile flows, such as the bile duct, gallbladder, and ampulla of Vater. Incidence rates are high in some countries, including Korea, and more than half of patients are diagnosed only at advanced stages when surgery is no longer an option. The survival period for advanced cholangiocarcinoma is just 11 to 15 months, and even among patients who undergo surgery aimed at complete cure, about half experience recurrence, making it a difficult cancer to treat. Until now, there have been very few studies that have traced, at the genomic level, the entire course of how cholangiocarcinoma occurs, recurs, or metastasizes.

The research team analyzed 72 samples—including normal tissue, precancerous lesions, primary tumors, and metastatic or recurrent tumors—collected from 17 patients with cholangiocarcinoma, using whole-exome sequencing (WES). Whole-exome sequencing is a technique that identifies mutations by analyzing the exome, which contains genetic information for protein synthesis. Based on this analysis, the team constructed patient-by-patient phylogenetic trees showing the order in which cancer cell groups (clones) emerged and branched, allowing them to trace the evolutionary path of the cancer.

The analysis revealed that mutations in key genes associated with cholangiocarcinoma—such as TP53, KRAS, and SMAD4—were already present in the precancerous lesions. This indicates that, even if the tissue is not yet cancerous in appearance, cancer-driving changes are already underway at the genetic level.

The researchers also observed that, within the precancerous lesions, certain groups of cells selectively survived and evolved into the primary tumor. Of the different cellular groups, those most advantaged for survival and proliferation were selected and came to dominate the lesion—a phenomenon the team described as ‘selective sweep’.

This kind of selective expansion continued during metastasis as well. Rather than all primary tumor cell groups evenly spreading, specific cell groups that were only a minority in the primary tumor established dominance in the metastatic organs. The team explained that, since cell environments differ from organ to organ, the cell groups most suited to survive in each new environment are selected.

It was also confirmed that, in recurred tumors after surgery, multiple cell groups from the primary tumor are retained. While cancer recurrence is typically explained as the proliferation of residual cancer cells somewhere in the body, this study found that several cell groups that made up the primary tumor remain together and participate in the recurrence.

This suggests that cancer recurrence can occur through a ‘polyclonal’ mechanism, in which several cell groups move and establish together, rather than arising from a single cancer cell. Moreover, genetic mutations that were identified as targets for treatment at the time of diagnosis were found to persist even after recurrence and metastasis. The research team explained, “When determining treatment strategies for patients with cholangiocarcinoma, it is important to identify major genetic mutations through precision genomic analysis from the diagnostic stage itself.”

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