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J. Hepatol., Jan 18 2025, S0168-8278(25)00013-3 | https://doi.org/10.1016/j.jhep.2025.01.007
Genomic and transcriptomic signatures of sequential carcinogenesis from papillary neoplasm to biliary tract cancer
Taek Chung 1,2, Seungho Oh 2,3, Jeongsoo Won 2,3, Jiho Park 2, Jeong Eun Yoo 1,4, Ho Kyoung Hwang 5, Gi Hong Choi 5, Chang Moo Kang 5, Dai Hoon Han 5, Sangwoo Kim 2,3,6, Young Nyun Park 1,4
1Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
2Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
5Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
6POSTECH Biotechnology Center, Pohang University of Science and Technology, Pohang, Republic of Korea
Corresponding authors: Sangwoo Kim, Young Nyun Park
1Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
2Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
5Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
6POSTECH Biotechnology Center, Pohang University of Science and Technology, Pohang, Republic of Korea
Corresponding authors: Sangwoo Kim, Young Nyun Park
Abstract
Background & aims: Papillary neoplasms of the biliary tree, including intraductal papillary neoplasms (IPN) and intracholecystic papillary neoplasms (ICPN), are recognized as precancerous lesions. However, the genetic characteristics underlying sequential carcinogenesis remain unclear.
Methods: 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.
Results: 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 IPN (42%, P<0.001), whereas SMAD4 mutations were enriched in extrahepatic IPN (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 IPN, in contrast to the heterogeneous distribution of SBS1, SBS2, SBS5, SBS13, SBS7b, and SBS23 in extrahepatic IPN and ICPN. 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 IPN/ICPN through sequential carcinogenesis, with the majority sharing driver mutations between IPN/ICPN and carcinoma. Furthermore, multifocal, independent carcinogenesis 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.
Conclusions: 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.
Impact and implications: Biliary tract cancer is a fatal malignancy. However, its genome-level sequential carcinogenesis 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 (IPN) of the bile duct and intracholecystic papillary neoplasms (ICPN), 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-genomics correlation, and potential therapeutic targets.
Methods: 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.
Results: 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 IPN (42%, P<0.001), whereas SMAD4 mutations were enriched in extrahepatic IPN (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 IPN, in contrast to the heterogeneous distribution of SBS1, SBS2, SBS5, SBS13, SBS7b, and SBS23 in extrahepatic IPN and ICPN. 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 IPN/ICPN through sequential carcinogenesis, with the majority sharing driver mutations between IPN/ICPN and carcinoma. Furthermore, multifocal, independent carcinogenesis 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.
Conclusions: 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.
Impact and implications: Biliary tract cancer is a fatal malignancy. However, its genome-level sequential carcinogenesis 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 (IPN) of the bile duct and intracholecystic papillary neoplasms (ICPN), 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-genomics correlation, and potential therapeutic targets.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-01-22)
- 국내 연구진
- 의약학 > 종양의학
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