Detecting and tracking circulating tumour DNA copy number profiles during first line chemotherapy in oesophagogastric adenocarcinoma
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ABSTRACT:
PROVIDER: EGAS00001003695 | EGA |
REPOSITORIES: EGA
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Project description:Small intestine neuroendocrine tumors are the commonest neuroendocrine tumors of the GI tract. Next gen sequencing of the whole exome was undertaken to identify SNPs and SCNA in these tumor samples. Subsequent bioinformatic anlaysis was done where the reads ratios of tumor/normal were log2 tranformed, segments indentified with DNAcopy (R package) and regions of SCNA were identified. Amplification of chr 4, 5, 14 and 20 was observed. The validation of these SCNAs was done with arrayCGH. The results of array CGH is in concordeance with the exome sequencing data.
2013-03-16 | GSE45190 | GEO
Project description:A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. We have reported high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several candidate genes and families are enriched among these regions of focal SCNA, including members of the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types.
2010-02-18 | GSE19399 | GEO
Project description:Small intestine neuroendocrine tumors are the commonest neuroendocrine tumors of the GI tract. Next gen sequencing of the whole exome was undertaken to identify SNPs and SCNA in these tumor samples. Subsequent bioinformatic anlaysis was done where the reads ratios of tumor/normal were log2 tranformed, segments indentified with DNAcopy (R package) and regions of SCNA were identified. Amplification of chr 4, 5, 14 and 20 was observed. The validation of these SCNAs was done with arrayCGH. The results of array CGH is in concordeance with the exome sequencing data. DNA from matched tumor and normal sample of SI-NETs was done by spin column method. Libraries were constructed and exome enriched for next gen sequencing. The same gDNA was hybridized with Cy5 and Cy3 and subsequent analysis was done. This study represents the CGH portion of the study.
2013-03-16 | E-GEOD-45190 | biostudies-arrayexpress
Project description:Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum chemotherapy.
2013-07-07 | GSE39281 | GEO
Project description:Metastatic urothelial carcinoma (UC) of the bladder is associated with multiple somatic copy number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic UC treated with platinum chemotherapy.
2013-07-07 | GSE39280 | GEO
Project description:DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.
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Project description:Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes chemotherapy exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.
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Project description:Study the effect of in vitro maturation system on the transcriptomics of bovine cumulus cells during incubation of first 6 hrs. 3 biological replicates of cumulus cells derived from cumulus oocyte complexes (COCs) after 6 hrs of in vitro matutaion(Ct-6H) vs. cumulus cells before maturation (Ct-0H, REFERENCE) were contrasted. Each replicate was subjected to a dye-swap procedure.
2015-07-01 | E-GEOD-67969 | biostudies-arrayexpress
Project description:Variable tumor cellularity can limit sensitivity and precision in comparative genomics, because differences in tumor content can result in misclassifying truncal mutations as region-specific private mutations in stroma-rich regions, especially when studying tissue specimens of mediocre tumor cellularity such as LUADs. To address this issue, we refined a nuclei flow-sorting approach by sorting nuclei based on ploidy and the LUAD lineage marker thyroid transcription factor 1 (TTF-1) and applied this method to investigate genome-wide somatic copy number aberrations (SCNA) and mutations of 409 cancer genes in 39 tumor populations obtained from 16 primary tumors and 21 matched metastases. This approach increased the mean tumor purity from 54% (range: 7-89%) of unsorted material to 92% (range: 79-99%) after sorting. Despite this rise in tumor purity, we detected limited genetic heterogeneity between primary tumors and their metastases. In fact, 88% of SCNAs and 80% of mutations were propagated from primary tumors to metastases and low allele frequency mutations accounted for much of the mutational heterogeneity. Even though the presence of SCNAs indicated a history of chromosomal instability (CIN) in all tumors, metastases did not have more SCNAs than primary tumors. Moreover, tumors with biallelic TP53 or ATM mutations had high numbers of SCNAs, yet they were associated with a low interlesional genetic heterogeneity. The results of our study thus provide evidence that most macroevolutionary events occur in primary tumors before metastatic dissemination and advocate for a limited degree of CIN over time and space in this cohort of LUADs. Sampling of primary tumors thus may suffice to detect most mutations and SCNAs. In addition, metastases but not primary tumors had seeded additional metastases in three of four patients; this provides a genomic rational for surgical treatment of such oligometastatic LUADs.
2018-09-11 | GSE119763 | GEO
Project description:A minimally parameterized mathematical model for low-dose metronomic
chemotherapy is formulated that takes into account angiogenic signaling between
the tumor and its vasculature and tumor inhibiting effects of tumor-immune system
interactions. The dynamical equations combine a model for tumor development under
angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune
system interactions by Stepanova. The dynamical properties of the model are analyzed.
Depending on the parameter values, the system encompasses a variety of medically
realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy
is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium
point) to situations when (ii) tumor dormancy is induced (a unique, globally asymp-
totically stable benign equilibrium point exists) to (iii) multi-stable situations that have
both persistent benign and malignant behaviors separated by the stable manifold of
an unstable equilibrium point and finally to (iv) situations when tumor growth can-
not be overcome by low-dose metronomic chemotherapy. The model forms a basis
for a more general study of chemotherapy when the main components of a tumor’s
microenvironment are taken into account
2020-02-03 | MODEL2002030001 | BioModels