title: Tumor evolution and intratumor heterogeneity of an epithelial ovarian cancer investigated using next-generation sequencing.
abstract: BACKGROUND
  The extent to which metastatic tumors further evolve by accumulating additional mutations is unclear and has yet to be addressed extensively using next-generation sequencing of high-grade serous ovarian cancer.
  
  
  METHODS
  Eleven spatially separated tumor samples from the primary tumor and associated metastatic sites and two normal samples were obtained from a Stage IIIC ovarian cancer patient during cytoreductive surgery prior to chemotherapy. Whole exome sequencing and copy number analysis were performed. Omental exomes were sequenced with a high depth of coverage to thoroughly explore the variants in metastatic lesions. Somatic mutations were further validated by ultra-deep targeted sequencing to sort out false positives and false negatives. Based on the somatic mutations and copy number variation profiles, a phylogenetic tree was generated to explore the evolutionary relationship among tumor samples.
  
  
  RESULTS
  Only 6% of the somatic mutations were present in every sample of a given case with TP53 as the only known mutant gene consistently present in all samples. Two non-spatial clusters of primary tumors (cluster P1 and P2), and a cluster of metastatic regions (cluster M) were identified. The patterns of mutations indicate that cluster P1 and P2 diverged in the early phase of tumorigenesis, and that metastatic cluster M originated from the common ancestral clone of cluster P1 with few somatic mutations and copy number variations.
  
  
  CONCLUSIONS
  Although a high level of intratumor heterogeneity was evident in high-grade serous ovarian cancer, our results suggest that transcoelomic metastasis arises with little accumulation of somatic mutations and copy number alterations in this patient.
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University, College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. yodrum682@gmail.com.
authors.forename: Jung-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Medicine, Seoul National University, Seoul, 110-744, Republic of Korea. neododari@gmail.com.
authors.forename: Jung-Ki
authors.initials: JK
authors.lastname: Yoon
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea. romanticet@snu.ac.kr.
authors.forename: Boyun
authors.initials: B
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea. skim245@snu.ac.kr.
authors.forename: Soochi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, 110-744, Republic of Korea. everest@snu.ac.kr.
authors.forename: Min A
authors.initials: MA
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Yonsei University, Room 437, Science Building, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, South Korea. limhs0915@gmail.com.
authors.forename: Hyeonseob
authors.initials: H
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Yonsei University, Room 437, Science Building, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, South Korea. duheebang@yonsei.ac.kr.
authors.forename: Duhee
authors.initials: D
authors.lastname: Bang
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University, College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. yssong@snu.ac.kr.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea. yssong@snu.ac.kr.|Major in Biomodulation, World Class University, Seoul National University, Seoul, 151-742, Republic of Korea. yssong@snu.ac.kr.
authors.forename: Yong-Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008954:Models, Biological; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*