Dataset Information

CTCR-OV03/CTCR-OV04 ovarian cancer

ABSTRACT: High-grade serous ovarian cancer (HGSOC) exhibits significant genomic heterogeneity within a patient at presentation. Recent work has suggested that this heterogeneity is linked to the development of resistance and disease progression in that chemotherapy selects for minor resistant subclones embodied in presentation disease leading to short progression-free survival and resistant relapse. Cell line models support this by showing that relapse is not an immediate descendant of presentation disease, but so far no immediate clinical evidence has been provided that convincingly demonstrates the origin of relapse. It is further still unclear what evolutionary processes shape the mutational landscape of HGSOC in vivo and to what extent the degree of genomic heterogeneity impacts a patient's clinical outcome. We address these questions by inferring evolutionary trees of metastatic disease from structural variations between 138 cancer samples obtained from 17 patients undergoing neoadjuvant chemotherapy for HGSOC. Using novel phylogenetic methods, we quantify genomic changes in the course of chemotherapy and the degree of clonal expansion and show that these indices determine patient outcome with high accuracy. We demonstrate that relapse is indeed a minor subclone of presentation disease by verifying that the focal NF1 deletion of a relapse case was already present at biopsy. By leveraging the information contained in the evolutionary trees, we unveil the etiology of genetic heterogeneity and the tumorigenic potential of HGSOC cell populations. This is the first comprehensive study showing the origin, strength and effect of genetic heterogeneity in HGSOC in a clinical setting. In addition to its immediate clinical significance, it strengthens previous statements that single sample biopsies are seemingly insufficient to predict disease progression and stresses the importance of establishing multiple sampling as a routine approach in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40546 | GEO | 2014/10/01

SECONDARY ACCESSION(S): PRJNA174252

REPOSITORIES: GEO

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Project description:High-grade serous ovarian cancer (HGSOC) exhibits significant genomic heterogeneity within a patient at presentation. Recent work has suggested that this heterogeneity is linked to the development of resistance and disease progression in that chemotherapy selects for minor resistant subclones embodied in presentation disease leading to short progression-free survival and resistant relapse. Cell line models support this by showing that relapse is not an immediate descendant of presentation disease, but so far no immediate clinical evidence has been provided that convincingly demonstrates the origin of relapse. It is further still unclear what evolutionary processes shape the mutational landscape of HGSOC in vivo and to what extent the degree of genomic heterogeneity impacts a patient's clinical outcome. We address these questions by inferring evolutionary trees of metastatic disease from structural variations between 138 cancer samples obtained from 17 patients undergoing neoadjuvant chemotherapy for HGSOC. Using novel phylogenetic methods, we quantify genomic changes in the course of chemotherapy and the degree of clonal expansion and show that these indices determine patient outcome with high accuracy. We demonstrate that relapse is indeed a minor subclone of presentation disease by verifying that the focal NF1 deletion of a relapse case was already present at biopsy. By leveraging the information contained in the evolutionary trees, we unveil the etiology of genetic heterogeneity and the tumorigenic potential of HGSOC cell populations. This is the first comprehensive study showing the origin, strength and effect of genetic heterogeneity in HGSOC in a clinical setting. In addition to its immediate clinical significance, it strengthens previous statements that single sample biopsies are seemingly insufficient to predict disease progression and stresses the importance of establishing multiple sampling as a routine approach in the clinic. Clinical data and tissue samples were collected on the prospective CTCR-OV03 and CTCR-OV04 clinical studies designed to identify biomarkers of heterogeneity.

Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.

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CTCR-OV03/CTCR-OV04 ovarian cancer

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