Tumor evolution and intratumor heterogeneity of an epithelial ovarian cancer investigated using next-generation sequencing

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• 作者：Jung-Yun Lee (1)
  Jung-Ki Yoon (2)
  Boyun Kim (3)
  Soochi Kim (3)
  Min A Kim (4)
  Hyeonseob Lim (5)
  Duhee Bang (5)
  Yong-Sang Song (1) (3) (6)
  
  1. Department of Obstetrics and Gynecology ; Seoul National University ; College of Medicine ; 101 Daehak-ro ; Jongno-gu ; Seoul ; 110-744 ; South Korea
  2. College of Medicine ; Seoul National University ; Seoul ; 110-744 ; Republic of Korea
  3. Cancer Research Institute ; Seoul National University College of Medicine ; Seoul ; 110-799 ; Republic of Korea
  4. Department of Pathology ; Seoul National University College of Medicine ; Seoul ; 110-744 ; Republic of Korea
  5. Department of Chemistry ; Yonsei University ; Room 437 ; Science Building ; 50 Yonsei-ro ; Seodaemun-gu ; Seoul ; 120-749 ; South Korea
  6. Major in Biomodulation ; World Class University ; Seoul National University ; Seoul ; 151-742 ; Republic of Korea
  
• 关键词：High grade serous ovarian cancer ; Whole exome sequencing ; Intratumor heterogeneity ; Peritoneal seeding ; Transcoelomic metastasis
• 刊名：BMC Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：15
• 期：1
• 全文大小：1,320 KB
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• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

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.