Journal of hepatology · 2025
Genomic and transcriptomic signatures of sequential carcinogenesis from papillary neoplasm to biliary tract cancer.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
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.
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 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.
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, 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.
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 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.
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, 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.