Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis

Q. Wei, Z. Ye, X. Zhong, L. Li, C. Wang, R. E. Myers, J. P. Palazzo, D. Fortuna, A. Yan, S. A. Waldman, Xi Chen, J. A. Posey, A. Basu-Mallick, B. H. Jiang, L. Hou, J. Shu, Y. Sun, J. Xing, Bingshan Li, Hushan Yang

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Background: Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. Patients and methods: We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. Results: CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. Conclusions: In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

Original languageEnglish (US)
Pages (from-to)2135-2141
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number9
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Colorectal cancer
  • Heterogeneity
  • Metastasis
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Wei, Q., Ye, Z., Zhong, X., Li, L., Wang, C., Myers, R. E., Palazzo, J. P., Fortuna, D., Yan, A., Waldman, S. A., Chen, X., Posey, J. A., Basu-Mallick, A., Jiang, B. H., Hou, L., Shu, J., Sun, Y., Xing, J., Li, B., & Yang, H. (2017). Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis. Annals of Oncology, 28(9), 2135-2141. https://doi.org/10.1093/annonc/mdx278