title: Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity.
abstract: Multifocal tumors developed either as independent tumors or as intrahepatic metastases, are very common in primary liver cancer. However, their molecular pathogenesis remains elusive. Herein, a patient with synchronous two hepatocellular carcinoma (HCC, designated as HCC-A and HCC-B) and one intrahepatic cholangiocarcinoma (ICC), as well as two postoperative recurrent tumors, was enrolled. Multiregional whole-exome sequencing was applied to these tumors to delineate the clonality and heterogeneity. The three primary tumors showed almost no overlaps in mutations and copy number variations. Within each tumor, multiregional sequencing data showed varied intratumoral heterogeneity (21.6% in HCC-A, 20.4% in HCC-B, 53.2% in ICC). The mutational profile of two recurrent tumors showed obvious similarity with HCC-A (86.7% and 86.6% respectively), rather than others, indicating that they originated from HCC-A. The evolutionary history of the two recurrent tumors indicated that intrahepatic micro-metastasis could be an early event during HCC progression. Notably, FAT4 was the only gene mutated in two primary HCCs and the recurrences. Mutation prevalence screen and functional experiments showed that FAT4, harboring somatic coding mutations in 26.7% of HCC, could potently inhibit growth and invasion of HCC cells. In HCC patients, both FAT4 expression and FAT4 mutational status significantly correlated with patient prognosis. Together, our findings suggest that spatial and temporal dissection of genomic alterations during the progression of multifocal liver cancer may help to elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Jie-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Xing
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Duan
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Liu-Xiao
authors.initials: LX
authors.lastname: Yang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shangai, P. R. China.
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.affiliation: School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Deng
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Zhen-Bin
authors.initials: ZB
authors.lastname: Ding
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.|Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.|Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, P. R. China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Xi
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000368:Aged; D015820:Cadherins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D015820:Cadherins; C534294:FAT4 protein, human; D025521:Tumor Suppressor Proteins
keywords: FAT4; hepatocellular carcinoma; intratumor heterogeneity; multifocal tumors; whole-exome sequencing