Spatial and temporal intra-tumoural heterogeneity in advanced High-Grade Serous Ovarian Cancer: implications for surgical and clinical outcomes
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PROVIDER: EGAS00001007164 | EGA |
REPOSITORIES: EGA
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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.
2014-10-01 | E-GEOD-40546 | biostudies-arrayexpress
Project description:This study aimed to generate a new panel of comprehensively, genomically characterized high-grade serous ovarian carcinoma (HGSOC) cell line and xenograft models. Multidimensional genomic data were generated and compared between cell lines/xenografts and the tumours they were derived from, indicating the cell lines/xenografts are highly similar to their patient-matched tumours. Cell line/xenograft data were also compared to TCGA ovarian tumours to show the cell lines are good models of clinical HGSOC. Illumina HT-12 v4 arrays were performed according to the manufacturer's directions on total RNA extracted from i) tumour cells purified from ovarian tumour ascites, and ii) established cell lines. Evaluation of the similarity in copy number/methylation/gene expression/mutational profiles of cell lines/tumours/xenografts was performed.
2016-08-11 | E-GEOD-71524 | biostudies-arrayexpress
Project description:This study aimed to generate a new panel of comprehensively, genomically characterized high-grade serous ovarian carcinoma (HGSOC) cell line and xenograft models. Multidimensional genomic data were generated and compared between cell lines/xenografts and the tumours they were derived from, indicating the cell lines/xenografts are highly similar to their patient-matched tumours. Cell line/xenograft data were also compared to TCGA ovarian tumours to show the cell lines are good models of clinical HGSOC. Illumina HumanMethylation450 arrays were performed according to the manufacturer's directions on DNA extracted from i) tumour cells purified from ovarian tumour ascites, and ii) established cell lines. Evaluation of the similarity in copy number/methylation/gene expression/mutational profiles of cell lines/tumours/xenografts was performed.
2016-08-11 | E-GEOD-71523 | biostudies-arrayexpress
Project description:This study aimed to generate a new panel of comprehensively, genomically characterized high-grade serous ovarian carcinoma (HGSOC) cell line and xenograft models. Multidimensional genomic data were generated and compared between cell lines/xenografts and the tumours they were derived from, indicating the cell lines/xenografts are highly similar to their patient-matched tumours. Cell line/xenograft data were also compared to TCGA ovarian tumours to show the cell lines are good models of clinical HGSOC. Affymetrix SNP 6 arrays were performed according to the manufacturer's instructions on genomic DNA extracted from i) tumour cells purified from ovarian tumour ascites, ii) established cell lines, iii) patient derived xenografts, and iv) lymphoblast lines. Evaluation of the similarity in copy number/methylation/gene expression/mutational profiles of cell lines/tumours/xenografts was performed.
2016-08-11 | E-GEOD-71522 | biostudies-arrayexpress
Project description:Dysregulation of the PI3K/AKT pathway is a common occurrence in ovarian carcinomas. Loss of the tumour suppressor PTEN in high-grade serous ovarian carcinoma (HGSOC) is associated with a patient subgroup with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We utilise long-term time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency does not affect proliferation but rather induces PI(3,4,5)P3-rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin as key ARF6 interactors regulating the PTEN loss-associated invasion phenotype. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin complexes to maintain invasive activity into the ECM. The expression of the ARF6-centred complex in HGSOC patients is inversely associated with outcome, allowing identification of patient groups with improved versus poor outcome. ARF6 may represent a new therapeutic vulnerability in PTEN-depleted HGSOC tumours.
2023-07-11 | PXD038305 | Pride
Project description:Introduction/ Background: The epigenome represents and adds another facet of complexity to cancer that needs to be understood to categorize patients into those at risk of disease, recurrence, or treatment failure. Our goal is to compare DNA methylation status between controls vs HGSOC, and relate it with clinical outcomes. Methodology: A retrospective review of our institution’s advanced/ recurrent HGSOC patients yielded 99 cases with good quality DNA and RNA. 12 normal fallopian tubes were also collected and used as controls. Infinium Illumina methylationEPIC was used to characterize DNA methylation status and RNA seq to evaluate gene expression. T- tests were used to compare methylation patterns between controls vs HGSOC, primary vs recurrent, and optimal vs suboptimal surgical outcomes. Spearman’s rank correlation was used to evaluate association between degree of methylation and expression of identified genes. Validation of our findings used the cancer genome atlas (TCGA) database followed by C-statistics to assess degree of agreement. Results: Out of 66,069 methylation probes that interrogate known genes, 5,852 probes were significantly different between normal and HGSOC. This includes genes that are enriched in several pathways such as the RAS signaling pathway. A similar analysis of the TCGA database showed 2,075 differentially methylated probes. 1,891 probes were significant in both datasets giving a 70.1% degree of agreement. When comparing differential DNA methylation between primary and recurrent disease, there were 57 probes which represent 17 genes that were significantly different. When comparing optimal vs suboptimal surgical outcomes, 99 probes were significantly different wherein 29 genes show expected inverse correlation between methylation status and gene expression. Conclusions: There are significant differences in methylation patterns between HGSOC and fallopian tubes, primary vs recurrent tissues, and optimal vs sub-optimal surgical outcomes. Cataloging these phenomena in a well characterized clinical population will aid in determining groupings for precision medicine treatment cohorts in the future.
2019-07-01 | GSE133556 | GEO
Project description:Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome in the management of high-grade serous ovarian cancer (HGSOC) patients. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) offers an alternate approach to management of HGSOC patients to achieve complete resection. This study assessed proteomic alterations in matched, chemotherapy naïve and NACT-treated patients tumors obtained from HGSOC patients with suboptimal (R1) versus optimal (R0) debulking at IDS. We describe distinct proteome profiles in pre- and post-NACT HGSOC tumors correlating with residual disease status providing prognostic biomarkers for residual disease at IDS as well as candidate proteins associated with NACT resistance warranting further pre-clinical investigation.
2022-10-05 | PXD031929 | Pride
Project description:Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma (PPGL) and medullary thyroid cancer (MTC), are caused by autosomal dominant mutations in a multitude of familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion but have undergone independent clonal evolution. Such tumours provide a unique opportunity to discover common co-operative changes required for tumorigenesis while controlling for the genetic background of the individual. We performed an in-depth genomic analysis of synchronous and metachronous tumours from five patients harbouring germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP-arrays we analyzed between two and four primary tumours from each patient. Furthermore, we applied multi-regional sampling to assess intra-tumoral heterogeneity and clonal evolution in two cases involving PPGL and MTC, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary PPGL. Convergent events also occurred during clonal evolution of metastatic MTC. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.
2017-02-02 | GSE94378 | GEO
Project description:The stabilization of MYCN by FOXR2 represents an alternative mechanism to MYCN amplification to increase MYCN protein levels. As such, FOXR2 expression identifies another subset of neuroblastoma patients with unfavorable clinical outcome. Background: Clinical outcomes of neuroblastoma patients range from spontaneous tumor regression to fatality. Hence, understanding the mechanisms that cause tumor progression are crucial for the treatment of patients. In this study, we show that FOXR2 activation identifies a subset of neuroblastoma tumors with unfavorable outcome and we investigate the mechanism how FOXR2 relates to poor outcome in patients.
2021-10-13 | GSE156092 | GEO
Project description:Tumour heterogeneity has been the main obstacle to the clinical efficacy of targeted and immunotherapy in cancer. An accurate understanding and recognition of tumour heterogeneity is critical in the clinical management of cancer patients. Here, we utilised single-cell RNA sequencing (scRNA-seq) to uncover the intra- and inter-tumoural heterogeneity of liver metastases from a patient with metastatic uveal melanoma.
2021-09-12 | GSE176029 | GEO