Introduction

The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.

Publications

  1. Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.
    Cite this
    Schwarz RF, Ng CK, Cooke SL, Newman S, Temple J, Piskorz AM, Gale D, Sayal K, Murtaza M, Baldwin PJ, Rosenfeld N, Earl HM, Sala E, Jimenez-Linan M, Parkinson CA, Markowetz F, Brenton JD, 2015-02-01 - PLoS Medicine
  2. Phylogenetic quantification of intra-tumour heterogeneity.
    Cite this
    Schwarz RF, Trinh A, Sipos B, Brenton JD, Goldman N, Markowetz F, 2014-04-01 - PLoS computational biology

Credits

  1. Roland F Schwarz
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  2. Charlotte K Y Ng
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  3. Susanna L Cooke
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  4. Scott Newman
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  5. Jillian Temple
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  6. Anna M Piskorz
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  7. Davina Gale
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  8. Karen Sayal
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  9. Muhammed Murtaza
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  10. Peter J Baldwin
    Developer

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom of Great Britain and Northern Ireland

  11. Nitzan Rosenfeld
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  12. Helena M Earl
    Developer

    Department of Oncology, Hutchison/MRC Research Centre, United Kingdom of Great Britain and Northern Ireland

  13. Evis Sala
    Developer

    University Department of Radiology, Addenbrooke's Hospital, United Kingdom of Great Britain and Northern Ireland

  14. Mercedes Jimenez-Linan
    Developer

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom of Great Britain and Northern Ireland

  15. Christine A Parkinson
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  16. Florian Markowetz
    Developer

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

  17. James D Brenton
    Investigator

    Cancer Research UK Cambridge Institute, University of Cambridge, United Kingdom of Great Britain and Northern Ireland

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Summary
AccessionBT000139
Tool TypeApplication
Category
PlatformsLinux/Unix
Technologies
User InterfaceTerminal Command Line
Download Count0
Country/RegionUnited Kingdom of Great Britain and Northern Ireland
Submitted ByJames D Brenton