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

Nature Genetics volume 48, pages 758–767 (2016)Cite this article

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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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References

  1. Ahmed, A.A. et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J. Pathol. 221, 49–56 (2010).

    Article  CAS  Google Scholar 

  2. Patch, A.-M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).

    Article  CAS  Google Scholar 

  3. Bashashati, A. et al. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J. Pathol. 231, 21–34 (2013).

    Article  CAS  Google Scholar 

  4. Ha, G. et al. TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data. Genome Res. 24, 1881–1893 (2014).

    Article  CAS  Google Scholar 

  5. Schwarz, R.F. et al. Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. PLoS Med. 12, e1001789 (2015).

    Article  Google Scholar 

  6. Jacobs, I.J. et al. Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation. J. Natl. Cancer Inst. 84, 1793–1798 (1992).

    Article  CAS  Google Scholar 

  7. Khalique, L. et al. The clonal evolution of metastases from primary serous epithelial ovarian cancers. Int. J. Cancer 124, 1579–1586 (2009).

    Article  CAS  Google Scholar 

  8. Lengyel, E. Ovarian cancer development and metastasis. Am. J. Pathol. 177, 1053–1064 (2010).

    Article  Google Scholar 

  9. Campbell, P.J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).

    Article  CAS  Google Scholar 

  10. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  Google Scholar 

  11. Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).

    Article  CAS  Google Scholar 

  12. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  Google Scholar 

  13. Eirew, P. et al. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518, 422–426 (2015).

    Article  CAS  Google Scholar 

  14. Gawad, C., Koh, W. & Quake, S.R. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc. Natl. Acad. Sci. USA 111, 17947–17952 (2014).

    Article  CAS  Google Scholar 

  15. Wang, Y. et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512, 155–160 (2014).

    Article  CAS  Google Scholar 

  16. Alekseyenko, A.V., Lee, C.J. & Suchard, M.A. Wagner and Dollo: a stochastic duet by composing two parsimonious solos. Syst. Biol. 57, 772–784 (2008).

    Article  Google Scholar 

  17. Ryder, R.J. & Nicholls, G.K. Missing data in a stochastic Dollo model for binary trait data, and its application to the dating of Proto-Indo-European. J. R. Stat. Soc. Ser. C Appl. Stat. 60, 71–92 (2011).

    Article  Google Scholar 

  18. Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  Google Scholar 

  19. Blei, D.M., Ng, A.Y. & Jordan, M.I. Latent dirichlet allocation. J. Machine Learning Res. 3, 993–1022 (2003).

    Google Scholar 

  20. Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004).

    Article  CAS  Google Scholar 

  21. Roth, A. et al. Clonal genotype and population structure inference from single-cell tumor sequencing. Nat. Methods http://dx.doi.org/10.1038/nmeth.3867 (2016).

  22. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  23. Hoogstraat, M. et al. Genomic and transcriptomic plasticity in treatment-naive ovarian cancer. Genome Res. 24, 200–211 (2014).

    Article  CAS  Google Scholar 

  24. Cooke, S.L. & Brenton, J.D. Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol. 12, 1169–1174 (2011).

    Article  CAS  Google Scholar 

  25. Schrader, K.A. et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet. Gynecol. 120, 235–240 (2012).

    Article  CAS  Google Scholar 

  26. McAlpine, J.N. et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod. Pathol. 25, 740–750 (2012).

    Article  CAS  Google Scholar 

  27. Roth, A. et al. PyClone: statistical inference of clonal population structure in cancer. Nat. Methods 11, 396–398 (2014).

    Article  CAS  Google Scholar 

Download references

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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Author notes

  1. Andrew McPherson and Andrew Roth: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada

    Andrew McPherson, Andrew Roth, Emma Laks, Tehmina Masud, Ali Bashashati, Allen W Zhang, Gavin Ha, Justina Biele, Damian Yap, Adrian Wan, Jaswinder Khattra, Maia A Smith, Sarah C Mullaly, Steve Kalloger, Karey Shumansky, Celia Siu, Jamie Rosner, David G Huntsman, Samuel Aparicio & Sohrab P Shah

  2. School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada

    Andrew McPherson

  3. Graduate Bioinformatics Training Program, University of British Columbia, Vancouver, British Columbia, Canada

    Andrew McPherson, Andrew Roth, Allen W Zhang, Gavin Ha & Maia A Smith

  4. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Andrew McPherson, Tehmina Masud, Cydney B Nielsen, David G Huntsman, Samuel Aparicio & Sohrab P Shah

  5. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, British Columbia, Canada

    Allen W Zhang

  6. Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Gavin Ha

  7. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Gavin Ha

  8. Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, British Columbia, Canada

    Leah M Prentice, Anthony Karnezis, Hector Li Chan, Julie Ho, Nataliya Melnyk, Janine Senz, Winnie Yang & David G Huntsman

  9. Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada

    Richard Moore, Andrew J Mungall, Marco A Marra & Sohrab P Shah

  10. Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada

    Alexandre Bouchard-Côté

  11. Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada

    C Blake Gilks

  12. Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, British Columbia, Canada

    Jessica N McAlpine

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  1. Andrew McPherson
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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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