Molecular evolution in different subtypes of multifocal hepatocellular carcinoma

作者全名："Tang, Xia; Xiang, Lei; Li, Qingshu; Shao, Yue; Wan, Li; Zhao, Dachun; Li, Xiaoyuan; Wu, Songfeng; Wang, Haijian; Li, Dewei; Ding, Keyue"

作者地址："[Tang, Xia; Wang, Haijian] Fudan Univ, Shanghai Pudong Hosp, Shanghai 200438, Peoples R China; [Tang, Xia; Wang, Haijian] Fudan Univ, Pudong Med Ctr, State Key Lab Genet Engn, Shanghai 200438, Peoples R China; [Tang, Xia; Wang, Haijian] Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, Shanghai 200438, Peoples R China; [Xiang, Lei; Wan, Li; Li, Dewei] Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Chongqing 400016, Peoples R China; [Li, Qingshu] Chongqing Med Univ, Dept Pathol, Chongqing 400016, Peoples R China; [Shao, Yue] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing 400016, Peoples R China; [Zhao, Dachun] Peking Union Med Coll Hosp, Dept Pathol, Beijing 100730, Peoples R China; [Li, Xiaoyuan] Peking Union Med Coll Hosp, Dept Oncol, Beijing 100730, Peoples R China; [Wu, Songfeng] Beijing Qinglian Biotech Co Ltd, Beijing 102206, Peoples R China; [Li, Dewei] Chongqing Univ Canc Hosp, Hepatobiliary & Pancreat Canc Ctr, Chongqing 400030, Peoples R China; [Ding, Keyue] Mayo Clin, Dept Cardiovasc Med, Rochester, MN 55905 USA"

通信作者："Wang, HJ (通讯作者)，Fudan Univ, Shanghai Pudong Hosp, Shanghai 200438, Peoples R China.; Wang, HJ (通讯作者)，Fudan Univ, Pudong Med Ctr, State Key Lab Genet Engn, Shanghai 200438, Peoples R China.; Wang, HJ (通讯作者)，Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, Shanghai 200438, Peoples R China.; Li, DW (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Chongqing 400016, Peoples R China.; Li, DW (通讯作者)，Chongqing Univ Canc Hosp, Hepatobiliary & Pancreat Canc Ctr, Chongqing 400030, Peoples R China.; Ding, KY (通讯作者)，Mayo Clin, Dept Cardiovasc Med, Rochester, MN 55905 USA."

来源：HEPATOLOGY INTERNATIONAL

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001000895200002

JCR分区：Q1

影响因子：5.9

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Intrahepatic metastasis; Multicentric occurrence; Tumor heterogeneity; Clonal evolution; Mutational signature; Quantitative metastatic timing; Preneoplastic arising clone

摘要："Background Multifocal hepatocellular carcinoma (MF-HCC) accounts for > 40% of HCCs, exhibiting a poor prognosis than single primary HCCs. Characterizing molecular features including dynamic changes of mutational signature along with clonal evolution, intrahepatic metastatic timing, and genetic footprint in the preneoplastic stage underlying different subtypes of MF-HCC are important for understanding their molecular evolution and developing a precision management strategy.Methods We conducted whole-exome sequencing in 74 tumor samples from spatially distinct regions in 35 resected lesions and adjacent noncancerous tissues from 11 patients, 15 histologically confirmed preneoplastic lesions, and six samples from peripheral blood mononuclear cells. A previously published MF-HCC cohort (n = 9) was included as an independent validation dataset. We combined well-established approaches to investigate tumor heterogeneity, intrahepatic metastatic timing, and molecular footprints in different subtypes of MF-HCCs.Results We classified MF-HCCs patients into three subtypes, including intrahepatic metastasis, multicentric occurrence, and mixed intrahepatic metastasis and multicentric occurrence. The dynamic changes in mutational signatures between tumor subclonal expansions demonstrated varied etiologies (e.g., aristolochic acid exposure) underlying the clonal progression in different MF-HCC subtypes. Furthermore, the clonal evolution in intrahepatic metastasis exhibited an early metastatic seeding at 10(-4)-0.01 cm(3) in primary tumor volume (below the limits of clinical detection), further validated in an independent cohort. In addition, mutational footprints in the preneoplastic lesions for multicentric occurrence patients revealed common preneoplastic arising clones, evidently being ancestors of different tumor lesions.Conclusion Our study comprehensively characterized the varied tumor clonal evolutionary history underlying different subtypes of MF-HCC and provided important implications for optimizing personalized clinical management for MF-HCC."

基金机构："National Natural Science Foundation of China, NSFC [81470898]"

基金资助正文："This study was supported by the National Natural Science Foundation of China, NSFC (No. 81470898 for D.L.)"