Homo sapiens
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PROVIDER: PRJNA398262 | ENA |
REPOSITORIES: ENA
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Project description:Aneuploidy from chromosomal instability is frequently detected in the vast majority of sporadic colorectal cancer patients and is believed to be an early driving force in disease progression. Despite this observation, the cellular advantages conferred by these cytogenetic alterations are poorly understood. We have isolated and immortalized non-transformed human colonic epithelial cells (HCECs) from non-cancerous biopsy tissue from a previous CRC patient undergoing routine colonoscopy. While these cells maintain a diploid karyotype under 2% serum conditions, we have isolated derivatives in serum-free culture with an extra copy of chromosome 7 (+7), a non-random trisomy detected in over 40% of human colorectal adenomas and carcinomas. We report here that +7 HCECs were not detectable in the initial cell population and appeared from an originally diploid population under serum-free culture conditions. The emergence of +7 cells correlates with a slight growth advantage that may be attributed to aberrant regulation of the epidermal growth factor receptor. We also provide evidence that +7 HCECs have defects in cell migration. A subpopulation with trisomy 20, another non-random chromosomal alteration in CRC, emerged following stable knockdown of TP53 and expression of oncogenic K-RASV12 in +7 HCECs. We describe isogenic HCECs that represent non-random cytogenetic changes occurring in sporadic colorectal cancer progression. These unique cellular reagents may serve as useful in vitro models for studying chromosomal instability-mediated tumorigenesis and the discovery of novel chemopreventive strategies.
2010-09-14 | GSE24092 | GEO
Project description:Intratumor heterogeneity is a major challenge in cancer treatment. To decipher patterns of chromosomal heterogeneity, we analyzed six colorectal cancer cell lines by multiplex interphase FISH. The mismatch repair deficient cell lines DLD-1 and HCT116 had the most stable copy numbers, whereas aneuploid cell lines displayed a higher degree of instability. We subsequently assessed the clonal evolution of a single cell in two aneuploid cell lines, SW480 and HT-29, which both have near-triploid karyotypes but different degrees of chromosomal instability. The clonal compositions of the single cell-derived daughter cell lines, as assessed by multiplex FISH, differed for HT-29 and SW480. Daughters of HT-29 were stable, clonal, and had little heterogeneity. Daughters of SW480 were more heterogeneous, with the single cell-derived daughter cell lines separating into two distinct populations with different ploidy (hyper-diploid and near-triploid), morphology, gene expression and tumorigenicity. To better understand the evolutionary trajectory for the two SW480 populations, we constructed phylogenetic trees which showed ongoing instability in the daughter cell lines.. When analyzing the evolutionary development over time, most single cell-derived daughter cell lines maintained their major clonal pattern, with the exception of one daughter of SW480 that showed a switch involving a loss of APC. Our meticulous analysis of the clonal evolution and composition of these colorectal cancer models shows that all chromosomes are subject to segregation errors, however, specific net genomic imbalances are maintained. Karyotype evolution is driven by the necessity to arrive at and maintain a specific plateau of chromosomal copy numbers as the drivers of carcinogenesis.
2018-05-01 | GSE102647 | GEO
Project description:Colorectal carcinoma (CRC) is often characterized by chromosomal instability (CIN) which has been associated with a poor prognosis. Disease-related de novo methylation often causes gene repression that may complement chromosomal losses or mutations. To compare CpG island methylation and chromosomal abnormalities in colorectal cancer, we determineded unbalanced chromosomal changes by aCGH of CRCs that were also profiled for aberrant de novo DNA methylation at 23,000 CpG islands of the human genome (Gebhard et al. 2010; and unpublished data). Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE25221: CpG island methylation in colorectal cancer GSE25228: Chromosomal abnormalities in colorectal cancer
2012-11-01 | E-GEOD-25229 | biostudies-arrayexpress
Project description:Single-cell chromosomal imbalances detection by array CGH
| PRJNA94905 | ENA
Project description:<p>We experimentally determined Mb-scale haplotypes from germline and cancer genome sequencing. Using a microfluidic process that partitions long DNA fragments into hundreds of thousands of barcoded reactions, we determined haplotype blocks from matched colorectal cancer samples in the delineation of haplotypes of allelic imbalances and other genomic instability events.</p>
| phs000898 | dbGaP
Project description:Colorectal carcinoma (CRC) is often characterized by chromosomal instability (CIN) which has been associated with a poor prognosis. Disease-related de novo methylation often causes gene repression that may complement chromosomal losses or mutations. To compare CpG island methylation and chromosomal abnormalities in colorectal cancer, we determineded unbalanced chromosomal changes by aCGH of CRCs that were also profiled for aberrant de novo DNA methylation at 23,000 CpG islands of the human genome (Gebhard et al. 2010; and unpublished data). This SuperSeries is composed of the SubSeries listed below.
2012-11-01 | GSE25229 | GEO
Project description:Telomere attrition ultimately leads to the activation of protective cellular responses such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we employ a liposarcoma model system to assay telomere maintenance mechanism-specific genetic alterations. A multiassay approach was used to assess the telomere maintenance mechanism(s) active in tumors. Genomic DNA from these samples was then analyzed by high resolution DNA mapping array in order to identify genetic alterations. Our data reveal a higher level of genome instability in ALT-positive tumors as compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance employed. We also identified genetic changes specific to the ALT mechanism, e.g., deletion of chromosome 1q32.2-q44, as well as changes that are underrepresented amongst ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. Experiment Overall Design: Goal: To study telomere maintenance and genetic alterations in liposarcoma using Affymetrix Mapping 50K Xba 240 GeneChip. Experiment Overall Design: Brief description: Telomere attrition ultimately leads to the activation of protective cellular responses such as apoptosis or senescence. Impairment of such mechanisms, however, can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. The high-density SNP-based microarrays (e.g., Affymetrix 100K arrays) can detect deletions, amplifications, and loss-of-heterozygosity on a genome in the liposarcoma samples. Chromosomal alterations of liposarcoma should provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. Experiment Overall Design: Quality control steps taken: Experiment Overall Design: a. PCR-based quality assessment of liposarcoma tissue genomic DNA Experiment Overall Design: b. Nanodrop analysis of preprocessed DNA prior to array hybridization Experiment Overall Design: c. Analysis of array call rates following hybridization (array experiments giving call rates of less than 80% were routinely repeated) Experiment Overall Design: Data extraction and processing protocols Experiment Overall Design: a. Image scanning hardware and software, and processing procedures and parameters: SNP array hybridization was detected using a GCS3000 scanner (Affymetrix). SNP calls and signal quantification were obtained with Gene Chip Operating System (GCOS) 1.2 and Affymetrix GDAS 3.0 with Dynamic Model Mapping Analysis by default settings (0.25) for both homozygote and heterozygote call thresholds. Copy number analyses were carried out using Affymetrix Chromosome Copy Number Analysis Tool (CNAT) 2.1 with a default genomic smoothing window setting of 0.5 Mb. Experiment Overall Design: b. Normalization, transformation and data selection procedures and parameters. Array data was normalized by a reference data set with CNAT. Experiment Overall Design: c. Definition of chromosomal aberration, amplification, deletion and LOH used for data interpretation: These definitions and their algorithms were described in detail by Huang, et al: Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics. 2004 May;1(4):287-99.
2008-06-16 | E-GEOD-8046 | biostudies-arrayexpress
Project description:Genomic instability, including microsatellite instability (MSI) and gross chromosomal abnormalities, has been described in sporadic colorectal cancer (CRC) and MSI has been suggested to have prognostic significance. However, there are few prognostically relevant biomarkers. Here we explore the potential of the analysis of DNA copy number changes at 1Mb resolution to predict survivorship in sporadic CRC. Keywords: Comparative Genomic Hybridization
2010-02-11 | GSE12520 | GEO
Project description:Details of the series are available in the publication Cardoso J. et al., âChromosomal instability in MYH- and APC-mutant adenomatous polypsâ, Cancer Research, accepted for publication. Abstract of the publication: âThe vast majority of colorectal cancers display genetic instability, either in the chromosomal (CIN) or microsatellite (MIN) forms. While CIN tumors are per definition aneuploid, MIN colorectal cancers, caused by loss of mismatch repair function, are usually near-diploid. Recently, bi-allelic germline mutations in the MYH gene, were found to be responsible for MAP (MYH associated polyposis), an autosomal recessive predisposition to multiple colorectal polyps, often indistinguishable from the dominant FAP (familial adenomatous polyposis) syndrome caused by inherited APC mutations. Here, we analyzed MYH- and APC-mutant polyps by combining laser-capture microdissection, isothermal genomic DNA amplification, and array-CGH (comparative genomic hybridization). Smoothed quantile regression methods were applied to the MAP and FAP genomic profiles to discriminate chromosomes predominantly affected by gains and losses. Up to 80% of the MAP polyps showed aneuploid changes, which is significantly higher than the 60% found among FAP polyps. Both MAP and FAP adenomas were characterized by frequent losses at chromosome 1p, 17, 19 and 22, and gains affecting chromosome 7 and 13. The observation that aneuploidy is already detectable at early stages of MYH-driven tumorigenesis raises the possibility that CIN may contribute significantly to accelerated tumor progression, increased cancer risk, and poor prognosis in MAP.â Details of the series are available in the publication Cardoso J. et al., âChromosomal instability in MYH- and APC-mutant adenomatous polypsâ, Cancer Research, accepted for publication.
2010-06-30 | E-GEOD-3898 | biostudies-arrayexpress