S-Space College of Medicine/School of Medicine (의과대학/대학원) Obstetrics & Gynecology (산부인과전공) Journal Papers (저널논문_산부인과학전공)
Tumor evolution and intratumor heterogeneity of an epithelial ovarian cancer investigated using next-generation sequencing
- Lee, Jung-Yun; Yoon, Jung-Ki; Kim, Boyun; Kim, Soochi; Kim, Min A; Lim, Hyeonseob; Bang, Duhee; Song, Yong-Sang
- Issue Date
- BioMed Central
- BMC Cancer, 15(1):85
- High grade serous ovarian cancer; Whole exome sequencing; Intratumor heterogeneity; Peritoneal seeding; Transcoelomic metastasis
- 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.
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.
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.
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.
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.