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. 2010 Sep 2;29(35):4905-13.
doi: 10.1038/onc.2010.245. Epub 2010 Jun 28.

Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma

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Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma

S L Cooke et al. Oncogene. .

Abstract

Resistance to chemotherapy in ovarian cancer is poorly understood. Evolutionary models of cancer predict that, following treatment, resistance emerges either because of outgrowth of an intrinsically resistant sub-clone or evolves in residual disease under the selective pressure of treatment. To investigate genetic evolution in high-grade serous (HGS) ovarian cancers, we first analysed cell line series derived from three cases of HGS carcinoma before and after platinum resistance had developed (PEO1, PEO4 and PEO6; PEA1 and PEA2; and PEO14 and PEO23). Analysis with 24-colour fluorescence in situ hybridisation and single nucleotide polymorphism (SNP) array comparative genomic hybridisation (CGH) showed mutually exclusive endoreduplication and loss of heterozygosity events in clones present at different time points in the same individual. This implies that platinum-sensitive and -resistant disease was not linearly related, but shared a common ancestor at an early stage of tumour development. Array CGH analysis of six paired pre- and post-neoadjuvant treatment HGS samples from the CTCR-OV01 clinical study did not show extensive copy number differences, suggesting that one clone was strongly dominant at presentation. These data show that cisplatin resistance in HGS carcinoma develops from pre-existing minor clones but that enrichment for these clones is not apparent during short-term chemotherapy treatment.

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Figures

Figure 1
Figure 1
Experimental design: Cell lines from 3 individuals established at different timepoints through disease progression were analysed. All patients received platinum-based chemotherapy. Grey boxes indicate platinum-resistant cell lines.
Figure 2
Figure 2
Probe-by-probe subtraction plots of the array CGH profiles for matched cell line pairs. (a) PEA2 – PEA1 (b) PEO4 – PEO1 and (c) PEO23 – PEO14 show differences (log2 ratio ≠ 0) on the majority of chromosomes. (d) PEO6 – PEO4 show genuine differences on chromosomes 4, 6 and 20 plus artefacts caused by homozygous deletions on chromosomes 9 and 16. All subtraction plots show increased noise around some telomeres and centromeres.
Figure 3
Figure 3
Array CGH profiles for patient OVO12 at (a) presentation and (b) debulking surgery. (c) Log2 ratio values of the debulking surgery profile (b) were scaled to match the range in the presentation array (a) to account for the difference in cellularity. (d) Difference in log ratio on a probe-by-probe basis between profiles of the two timepoints after correcting for cellularity. Alternate chromosomes are shown in different colours. The majority of the genome shows no difference between the samples but the negative difference in the log2 ratio for the X chromosome indicates gain in the debulking surgery sample. Several chromosomes, e.g. 1p, 7p, show differences in a very small number of markers immediately adjacent to the telomere or centromere, possibly as a common artefact due to increased noise in these regions.

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