Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.
<h4>Background</h4>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...
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Public Library of Science (PLoS)
2015-02-01
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| Online Access: | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001789&type=printable |
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| author | Roland F Schwarz Charlotte K Y Ng Susanna L Cooke Scott Newman Jillian Temple Anna M Piskorz Davina Gale Karen Sayal Muhammed Murtaza Peter J Baldwin Nitzan Rosenfeld Helena M Earl Evis Sala Mercedes Jimenez-Linan Christine A Parkinson Florian Markowetz James D Brenton |
| author_facet | Roland F Schwarz Charlotte K Y Ng Susanna L Cooke Scott Newman Jillian Temple Anna M Piskorz Davina Gale Karen Sayal Muhammed Murtaza Peter J Baldwin Nitzan Rosenfeld Helena M Earl Evis Sala Mercedes Jimenez-Linan Christine A Parkinson Florian Markowetz James D Brenton |
| author_sort | Roland F Schwarz |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-0a04b45ee3a2448488392ea351cd23be |
| institution | OA Journals |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2015-02-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-0a04b45ee3a2448488392ea351cd23be2025-08-20T02:22:20ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762015-02-01122e100178910.1371/journal.pmed.1001789Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.Roland F SchwarzCharlotte K Y NgSusanna L CookeScott NewmanJillian TempleAnna M PiskorzDavina GaleKaren SayalMuhammed MurtazaPeter J BaldwinNitzan RosenfeldHelena M EarlEvis SalaMercedes Jimenez-LinanChristine A ParkinsonFlorian MarkowetzJames D Brenton<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001789&type=printable |
| spellingShingle | Roland F Schwarz Charlotte K Y Ng Susanna L Cooke Scott Newman Jillian Temple Anna M Piskorz Davina Gale Karen Sayal Muhammed Murtaza Peter J Baldwin Nitzan Rosenfeld Helena M Earl Evis Sala Mercedes Jimenez-Linan Christine A Parkinson Florian Markowetz James D Brenton Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. PLoS Medicine |
| title | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. |
| title_full | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. |
| title_fullStr | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. |
| title_full_unstemmed | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. |
| title_short | Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. |
| title_sort | spatial and temporal heterogeneity in high grade serous ovarian cancer a phylogenetic analysis |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001789&type=printable |
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