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

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Authors
Lee, Jung-Yun; Yoon, Jung-Ki; Kim, Boyun; Kim, Soochi; Kim, Min A; Lim, Hyeonseob; Bang, Duhee; Song, Yong-Sang
Issue Date
2015-02-26
Publisher
BioMed Central
Citation
BMC Cancer, 15(1):85
Keywords
High grade serous ovarian cancerWhole exome sequencingIntratumor heterogeneityPeritoneal seedingTranscoelomic metastasis
Description
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.
Abstract
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.
Language
English
URI
http://hdl.handle.net/10371/100516
DOI
https://doi.org/10.1186/s12885-015-1077-4
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College of Medicine/School of Medicine (의과대학/대학원)Obstetrics & Gynecology (산부인과전공)Journal Papers (저널논문_산부인과학전공)
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