A team led by Prof. Young Nyun Park (Yonsei University, Seoul) offers a comprehensive look into the genetic and transcriptomic landscape of intraductal/intracholecystic papillary neoplasms of the bile duct (IPN/ICPN), shedding new light on an often-overlooked biliary tract cancer with very poor prognosis. Biliary tract cancer commonly presents at a late stage, when surgical intervention is no longer feasible, and there are few effective targeted treatment options. IPN/ICPNs are recognized as a significant precursor to cholangiocarcinoma, yet little was known about how specific genetic alterations drive these tumors to become invasive cancer.

By conducting whole-exome sequencing (WES) on tissue samples from 166 patients and performing spatial transcriptomic analysis on nine representative tumors, the team has revealed that IPN/ICPNs exhibit striking genetic differences based on their anatomical site: intrahepatic bile ducts, extrahepatic bile ducts, or the gallbladder. While intrahepatic IPNs frequently harbor KRAS mutations (42%), extrahepatic lesions more commonly show SMAD4 (21%) and TP53 (30%) alterations, and ICPNs display a distinct pattern dominated by CTNNB1 mutations (23%). Mutational signature analysis confirmed that each location follows a unique mechanism of oncogenic changes.

The team also compared precursor lesions and their corresponding invasive cancer regions, finding that while many key driver mutations appear early, additional copy number aberrations and new mutations—often affecting cell morphology, angiogenesis, and growth factor responses—accumulate during progression. Notably, spatial transcriptomic data indicate that stepwise alterations in extracellular matrix organization and growth factor signaling play crucial roles in malignant transformation.

As the largest integrated genomic study of IPN/ICPN and cholangiocarcinoma to date, this work paves the way for more precise diagnostic panels and informs the development of new therapeutic strategies, ultimately aiming to improve outcomes in this challenging disease.

Genetic mutations and aberrant gene expression patterns during the progression of biliary papillary 

neoplasm to invasive carcinoma

[Reference] Chung, T. et al., Genomic and transcriptomic signatures of sequential carcinogenesis from papillary neoplasm to biliary tract cancer. Journal of Hepatology (2025). https://doi.org/10.1016/j.jhep.2025.01.007

[Main Author] Taek Chung (Yonsei University), Sangwoo Kim (Yonsei University), Young Nyun Park (Yonsei University) 

* Contact : Professor Young Nyun Park (young0608@yuhs.ac)