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| Item Type: | Article |
|---|---|
| Title: | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis |
| Creators Name: | Schwarz, R.F., Ng, C.K.Y., Cooke, S.L., Newman, S., Temple, J., Piskorz, A.M., Gale, D., Sayal, K., Murtaza, M., Baldwin, P.J., Rosenfeld, N., Earl, H.M., Sala, E., Jimenez-Linan, M., Parkinson, C.A., Markowetz, F. and Brenton, J.D. |
| Abstract: | Background: 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. Methods and Findings: 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. Conclusions: 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. |
| Keywords: | Algorithms, Alleles, Disease-Free Survival, Genetic Variation, Glandular and Epithelial Neoplasms, Neoplasm DNA, Neoplasm Drug Resistance, Ovarian Neoplasms, Phylogeny, Platinum |
| Source: | PLoS Medicine |
| ISSN: | 1549-1277 |
| Publisher: | Public Library of Science |
| Volume: | 12 |
| Number: | 2 |
| Page Range: | e1001789 |
| Date: | 24 February 2015 |
| Additional Information: | Erratum in: Nature 568(7751): E4. |
| Official Publication: | https://doi.org/10.1371/journal.pmed.1001789 |
| PubMed: | View item in PubMed |
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