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Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer

Abstract

We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.

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Figure 1: SNV phylogenies for seven patients with HGSOvCa.
Figure 2: Evidence of samples composed of divergent clonal mixtures.
Figure 3: Single-nucleus sequencing of patients with samples containing mixtures of divergent lineages.
Figure 4: Clone phylogenies and sample clone mixtures.
Figure 5: Analysis of clonal phylogenies and clone mixtures.
Figure 6: Examples of convergent evolution of copy number.

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Acknowledgements

We thank V. Earle for the artwork depicting anatomical sites sampled in the study. We acknowledge generous long-term funding support provided by the BC Cancer Foundation. In addition, the groups of S.P.S. and S.A. receive operating funds from the Canadian Breast Cancer Foundation, the Canadian Cancer Society Research Institute (grant 701584), the Terry Fox Research Institute, Genome Canada/Genome BC (173-CIC and 177-EVO), the Canadian Institutes for Health Research (CIHR) (MOP-115170, MOP-126119, and FDN-143246), a new investigator grant to J.N.M. (MSH-261515), and a TFRI new investigator award to S.P.S. S.P.S. and S.A. are supported by Canada Research Chairs. S.P.S. is a Michael Smith Foundation for Health Research scholar. A.M. is supported by a NSERC CGS scholarship. A.R. is supported by a CIHR CGS scholarship. T.M. is supported by a Canadian Breast Cancer Foundation British Columbia/Yukon Postdoctoral Fellowship.

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Authors

Contributions

A.M. and A.R. performed algorithm development and software implementation and led the data analysis. G.H., A.W.Z., K.S., C.S., J.R., and A.B. performed data analysis and bioinformatics. E.L., T.M., J.B., D.Y., A.W., and J.K. performed single-nucleus sequencing. L.M.P., S.K., J.S., and W.Y. performed sample preparation and validation experiments. M.A.S. and C.B.N. performed data visualization. A.K., H.L.C., J.H., and N.M. performed immunohistochemistry and FISH analyses. R.M., A.J.M., and M.A.M. performed library construction and genome sequencing. C.B.G. and D.G.H. analyzed molecular and histological pathology. A.B.-C. contributed to algorithm development. J.N.M. performed surgery and tumor banking and was a clinical leader. S.C.M. edited the manuscript. A.M., A.R., S.A., and S.P.S. wrote the manuscript. S.A. oversaw experimental design and single-cell sequencing. S.P.S. is the senior responsible author and conceived the project and provided oversight.

Corresponding authors

Correspondence to Samuel Aparicio or Sohrab P Shah.

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The authors declare no competing financial interests.

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McPherson, A., Roth, A., Laks, E. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat Genet 48, 758–767 (2016). https://doi.org/10.1038/ng.3573

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