title: The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhai
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore.
authors.forename: Tony Kiat-Hon
authors.initials: TK
authors.lastname: Lim
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Su-Ting
authors.initials: ST
authors.lastname: Phang
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Zenia
authors.identifier: 0000-0003-1182-0023
authors.initials: Z
authors.lastname: Tiang
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Guan
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Ming-Hwee
authors.initials: MH
authors.lastname: Ng
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Jia Qi
authors.initials: JQ
authors.lastname: Lim
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Fei
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Zheng
authors.identifier: 0000-0002-7060-2213
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Poh Yong
authors.initials: PY
authors.lastname: Ng
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Goh
authors.affiliation: Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore.
authors.forename: Alexander Yaw-Fui
authors.initials: AY
authors.lastname: Chung
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Su-Pin
authors.initials: SP
authors.lastname: Choo
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.
authors.forename: Wendy Wei-Jia
authors.initials: WW
authors.lastname: Soon
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.|School of Computing, National University of Singapore, 13 Computing Drive, Singapore 117417, Singapore.
authors.forename: Ken Wing-Kin
authors.initials: KW
authors.lastname: Sung
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore.|Cardiovascular Research Institute, National University of Singapore, National University Healthcare System, Singapore 119228, Singapore.
authors.forename: Roger Sik-Yin
authors.initials: RS
authors.lastname: Foo
authors.affiliation: Division of Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore.|Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore 169608, Singapore.|Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Pierce Kah-Hoe
authors.initials: PK
authors.lastname: Chow
mesh_terms: D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000821:virology; D056915:DNA Copy Number Variations / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D010641:Phenotype; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D016662:Virus Integration