title: Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity.
abstract: OBJECTIVE
  The intratumoral heterogeneity (ITH) and the evolution of genomic architectures associated with the development of distant metastases are not well understood in colorectal cancers.
  
  
  METHODS
  We performed multiregion biopsies of primary and liver metastatic regions from five colorectal cancers with whole-exome sequencing and copy number profiling.
  
  
  RESULTS
  In addition to a substantial level of genetic ITH, multiregion genetic profiling identifies the subclonal mutational architecture, leading to the region-based or spatial categorization of somatic mutations and the inference of intratumoral evolutionary history of cancers. The universal mutations (those observed in all the regional biopsies) are enriched in known cancer genes such as APC and TP53 with distinct mutational spectra compared with biopsy- or region-specific mutations, suggesting that major operative mutational mechanisms and their selective pressures are not constant across the metastatic progression. The phylogenies inferred from genomic data show branching evolutionary patterns where some primary biopsies are often segregated with metastastic lesions. Our analyses also revealed that copy number changes such as the chromosomal gains of c-MYC and chromothripsis can be region specific and the potential source of genetic ITH.
  
  
  CONCLUSIONS
  Our data show that the genetic ITH is prevalent in colorectal cancer serving as a potential driving force to generate metastasis-initiating clones and also as a means to infer the intratumoral evolutionary history of cancers. The paucity of recurrent metastasis-clonal events suggests that colorectal cancer distant metastases may not follow a uniform course of genomic evolution, which should be considered in the genetic diagnosis and the selection of therapeutic targets for the advanced colorectal cancer.
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung Hak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: In-Pyo
authors.initials: IP
authors.lastname: Baek
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Je-Keun
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. yejun@catholic.ac.kr suhulee@catholic.ac.kr.
authors.forename: Sug-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. yejun@catholic.ac.kr suhulee@catholic.ac.kr.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
mesh_terms: D001706:Biopsy; D002874:Chromosome Mapping; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D018895:Microsatellite Repeats; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010802:Phylogeny