Chung Taek, Oh Seungho, Won Jeongsoo, Park Jiho, Yoo Jeong Eun, Hwang Ho Kyoung, Choi Gi Hong, Kang Chang Moo, Han Dai Hoon, Kim Sangwoo, Park Young Nyun
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
J Hepatol. 2025 Jul;83(1):119-130. doi: 10.1016/j.jhep.2025.01.007. Epub 2025 Jan 18.
BACKGROUND & AIMS: Papillary neoplasms of the biliary tree, including intraductal papillary neoplasms (IPNs) and intracholecystic papillary neoplasms (ICPNs), are recognized as precancerous lesions. However, the genetic characteristics underlying sequential carcinogenesis remain unclear.
Whole-exome sequencing was performed on 166 neoplasms (33 intrahepatic IPNs, 44 extrahepatic IPNs, and 89 ICPNs), and 41 associated carcinomas. Nine available cases were also subjected to spatial transcriptomic analysis.
Mutations in the MAPK (48%), genomic integrity maintenance (42%), and Wnt/β-catenin (33%) pathways were prevalent in intrahepatic IPNs, extrahepatic IPNs, and ICPNs, respectively. KRAS mutations were enriched in intrahepatic IPNs (42%, p <0.001), whereas SMAD4 mutations were enriched in extrahepatic IPNs (21%, p = 0.005). ICPNs frequently exhibit CTNNB1 mutations, particularly in low-grade lesions. Mutational signature analysis revealed that SBS1 and SBS5 signatures were homogeneously enriched in intrahepatic IPNs, in contrast to the heterogeneous distribution of SBS1, SBS2, SBS5, SBS13, SBS7b, and SBS23 in extrahepatic IPNs and ICPNs. Copy number aberrations gradually increased from low-to high-grade intraepithelial neoplasia and eventually to carcinoma. Phylogenetic analysis revealed that 89% of carcinomas were derived from IPNs/ICPNs through sequential carcinogenesis, with the majority sharing driver mutations between the IPN/ICPN and the carcinoma. Furthermore, multifocal, independent carcinogenic events were observed in IPNs/ICPNs, resulting in mutationally distinct carcinoma lesions. Carcinogenesis of IPN/ICPN occurs in multiple subclones through mutational accumulation and transcriptomic alterations that affect vascular development, cell morphogenesis, extracellular matrix organization, and growth factor response.
With the largest IPN/ICPN cohort reported to date, our study provides a genome- and spatial transcriptome-level portrait of sequential carcinogenesis and differences in the anatomical location of biliary papillary neoplasms.
Biliary tract cancer is a fatal malignancy. However, the genome-level sequential progression from intraepithelial neoplasia to carcinoma has not yet been evaluated in a sufficiently large cohort. Papillary lesions of the bile duct and gallbladder are collectively termed intraductal papillary neoplasms of the bile duct and intracholecystic papillary neoplasms, respectively. They are primarily diagnosed based on histopathological studies. This study provides a comprehensive mutational and spatial transcriptomic landscape of papillary neoplasms of the bile duct and gallbladder. The results of this study offer insights into the mechanism of sequential carcinogenesis in papillary biliary tract tumors, pathology-genomic correlations, and potential therapeutic targets.
胆管乳头状肿瘤，包括导管内乳头状肿瘤（IPN）和胆囊内乳头状肿瘤（ICPN），被认为是癌前病变。然而，其连续致癌的遗传特征仍不清楚。
对166例肿瘤（33例肝内IPN、44例肝外IPN和89例ICPN）以及41例相关癌进行了全外显子测序。对9例可获取的病例还进行了空间转录组分析。
丝裂原活化蛋白激酶（MAPK）通路突变（48%）、基因组完整性维持通路突变（42%）和Wnt/β-连环蛋白通路突变（33%）分别在肝内IPN、肝外IPN和ICPN中普遍存在。KRAS突变在肝内IPN中富集（42%，p<0.001），而SMAD4突变在肝外IPN中富集（21%，p = 0.005）。ICPN经常出现CTNNB1突变，尤其是在低级别病变中。突变特征分析显示，SBS1和SBS5特征在肝内IPN中均匀富集，而在肝外IPN和ICPN中，SBS1、SBS2、SBS5、SBS13、SBS7b和SBS23呈异质性分布。拷贝数畸变从低级别到高级别上皮内瘤变逐渐增加，最终发展为癌。系统发育分析显示，89%的癌是通过连续致癌从IPN/ICPN衍生而来，大多数在IPN/ICPN和癌之间共享驱动突变。此外，在IPN/ICPN中观察到多灶性、独立的致癌事件，导致癌病变在突变上不同。IPN/ICPN的致癌过程通过突变积累和转录组改变发生在多个亚克隆中，这些改变影响血管发育、细胞形态发生、细胞外基质组织和生长因子反应。
我们的研究是迄今为止报道的最大规模的IPN/ICPN队列研究，提供了胆管乳头状肿瘤连续致癌的基因组和空间转录组水平的全貌以及解剖位置差异。
胆管癌是一种致命的恶性肿瘤。然而，上皮内瘤变到癌的基因组水平连续进展尚未在足够大的队列中进行评估。胆管和胆囊的乳头状病变分别统称为胆管导管内乳头状肿瘤和胆囊内乳头状肿瘤。它们主要通过组织病理学研究进行诊断。本研究提供了胆管和胆囊乳头状肿瘤全面的突变和空间转录组图谱。本研究结果为胆管乳头状肿瘤连续致癌机制、病理-基因组相关性及潜在治疗靶点提供了见解。
