Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Alana Welm
PROVIDER: E-GEOD-32532 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. Single replicates of genomic DNA from 12 human breast cancer tumors and xenografts of those tumors in immunodeficient mice were hybridized to Affymetrix Human SNP 6.0 genotyping arrays.
2011-10-22 | E-GEOD-32530 | biostudies-arrayexpress
Project description:Hypothesis: Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups. Results: Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n=50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term survivors. In squamous cell carcinoma (n=28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, mRNA expression levels of corresponding genes were increased or decreased, respectively. Conclusion: Comprehensive tumor profiling permits the integration of genomic, histologic and clinical data. We identified gene copy number gains and losses, with corresponding changes in mRNA levels, that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung. Short-term (<20 months; n=53) and long-term survivors (>58 months;n=47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh-frozen tumor specimens. The samples were analyzed using high-resolution SNP-array technology. The molecular data was combined with information on clinical parameters.
2011-11-01 | E-GEOD-28572 | biostudies-arrayexpress
Project description:The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation, however, instances of CD133- cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133+ and CD133- self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stem-like cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. Keywords: Expression and copy number analysis of glioblastomas and neurosphere forming derivative cell lines of same. DNA analysis and Expression profiling: DNA from patient tumor mincates was profiled for copy number changes on Affymetrix 500k chips and sequenced for mutations in exons 4-8 of p53 and exons 5&6 of PTEN. For determination of amplification, samples with mean relative copy number estimates of >3 for SNPs residing within the locus were scored as amplified. Copy number losses were determined using data from 30 SNPs within or immediately flanking the locus of interest. Relative copy number losses that were statistically significant at the p<.001 level were scored as losses regardless of the magnitude of the alteration. DNA from neurosphere lines was analyzed for copy number alterations by profiling on Agilent 244K arrays. Relative copy number estimates were determined using the GLAD segmentation algorithm. For expression profiling, RNA was extracted as previously described (Phillips et al., 2006) and profiled on Agilent WHG (for patient samples) or WHG 4x44 chips (for neurosphere lines and grafts) according to the manufacturer's (Agilent technologies, Palo Alto CA) protocol.
2010-04-21 | E-GEOD-19612 | biostudies-arrayexpress
Project description:The accurate mapping of recurring DNA copy number aberrations (CNAs), a hallmark feature of the cancer genome, has facilitated the discovery of tumor suppressor genes and oncogenes. Microarray-based assays designed to detect these chromosomal copy number alterations on a genome-wide and high-resolution scale have emerged as a cornerstone technology in the genomic era. The diversity of commercially-available platforms prompted a systematic comparison of five copy number profiling assays for their ability to detect 2-fold copy number gain and loss (4n or 1n, respectively) as well as focal high-amplitude CNAs. Here, using a collection of established human melanoma cell lines, we defined the reproducibility, absolute signals, signal:noise, false-positive and false-negative rates for each of the five assays against ground-truth defined by Spectral Karyotyping (SKY), in addition to comparing the concordance of CNAs detection by two high-resolution Agilent and Affymetrix microarray platforms. Our analyses concluded that the Agilentâs 60mer oligo-microarray with probe design optimized for genomic hybridization offers the highest sensitivity and specificity [area under Receiver Operator Characteristic (ROC) curve >0.99] while Affymetrixâs SNP microarray appears to offer better detection of CNAs in gene-poor region. Availability of these comparison results should guide study design decisions and facilitate further computational development. Keywords: comparative genomic hybridization We generated copy number profiles of a defined set of tumor cell lines on five oligo-microarray-based assays of three platforms (Agilent, Affymetrix and NimbleGen) and determined the reproducibility, signal and noise as well as sensitivity and specificity of each in detecting two-fold signals based on SKY-defined aberrations as ground-truth for comparison. In addition, high-density microarray assays from Agilent and Affymetrix platforms were further compared for definition of CNAs in an independent dataset using published analytical approaches. All arrays were run from the same DNA harvest from respective cell lines. Each array was run according to the protocol of the manufacturer.
2010-05-26 | E-GEOD-7822 | biostudies-arrayexpress
Project description:A common aim of pharmacogenomic studies that employ genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous investigations of lapatinib, a selective dual-kinase inhibitor of EGFR and HER2 tyrosine kinases, have demonstrated predictable relationships between the activity of these genes and response. Under the hypothesis that additional genes may play a role in promoting sensitivity, a predictive model for lapatinib sensitivity was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model, which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model, which achieved area under the Receiver Operating Characteristic (ROC) curve of ~0.85 (80% confidence interval: 0.70–0.98; P<0.01), and correctly classified the sensitivity status of 8/10 head and neck cancer cell lines. This study demonstrates that previously described biomarkers of lapatinib sensitivity, including copy number gains of EGFR and HER2, can be discovered as powerful predictors of response using novel genomic assays in an unbiased manner. Further, these results demonstrate the utility of DNA copy number profiles in pharmacogenomic studies. Keywords: Comparative Genomic Hybridization Basal DNA copy number profiles were derived from Affymetrix 'SNP chips' for a panel of 34 tumor derived cell lines. Each of these cell lines were tested for their degree of sensitivity to lapatinib. Specific DNA alterations associating with lapatinib sensitivity were identified using a training set consisting of 24 of these lines. A predictive model was constructed from these loci. The remaining 10 lines were used to test the model performance. A panel of chips (n = 12) assayed with germline DNA served as a reference in order to calculate the test/reference ratios reported in the Sample table VALUE columns. The 'reference' Samples for the 500K and 100K assays are as follows: 500K: GSM188024, GSM188025, GSM188026, GSM188027, GSM188028, GSM188029, GSM188030, GSM188031, GSM188032, GSM188033, GSM188034, GSM188035, GSM188048, GSM188049, GSM188050, GSM188051, GSM188052, GSM188053, GSM188054, GSM188055, GSM188056, GSM188057, GSM188058, GSM188059 100K: GSM187950, GSM187951, GSM187952, GSM187953, GSM187954, GSM187955, GSM187956, GSM187957, GSM187958, GSM187959, GSM187960, GSM187961, GSM187949, GSM187948, GSM187946, GSM187947, GSM187945, GSM187944, GSM187943, GSM187942, GSM187941, GSM187940, GSM187939, GSM187938
2008-03-10 | E-GEOD-9585 | biostudies-arrayexpress
Project description:Copy number profiling of 36 ovarian tumors on Affymetrix 100K SNP arrays Thirty-six ovarian tumors were profiled for copy-number alterations with the Affymetrix 100K Mapping Array. Copy number profiling of 36 ovarian tumors on Affymetrix 500K SNP arrays Sixteen ovary tumors were profiled for copy-number alterations with the high-resolution Affymetrix 500K Mapping Array. Affymetrix 100K Mapping Array intensity signal CEL files were processed by dChip 2005 (Build date Nov 30, 2005) using the PM/MM difference model and invariant set normalization. Each probe set was mapped to the genome, NCBI assembly version 36, using annotation provided by the Affymetrix web site. The log2 ratios were centered to a median of zero and segmented using the GLAD package for the R statistical environment. Copy number was calculated as power(2,log2ratio + 1). Affymetrix 500K Mapping Array intensity signal CEL files were processed by dChip 2005 (Build date Nov 30, 2005) using the PM/MM difference model and invariant set normalization. Forty-eight normal samples were downloaded from the Affymetrix website (http://www.affymetrix.com/support/technical/byproduct.affx?product=500k) and analyzed at the same time. One CEL file for each set (Sty and Nsp) with the median signal intensity across the set was selected as the reference array. The dChip-normalized signal intensities were converted to log2 ratios and segmented as follows. For each autosomal probe set, the log2 tumor/normal ratio of each tumor sample was calculated using the average intensity for each probe set in the normal set. For Chromosome X, the average of the 20 normal female samples was used. Each probe set was mapped to the genome, NCBI assembly version 36, using annotation provided by the Affymetrix web site. The log2 ratios were centered to a median of zero and segmented using the GLAD package for the R statistical environment. Copy number was calculated as power(2,log2ratio + 1).
2010-12-16 | E-GEOD-26075 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE28571: Gene Copy Number Aberrations are Associated with Survival in Histological Subgroups of Non-Small Cell Lung Cancer (expression data) GSE28572: Gene Copy Number Aberrations are Associated with Survival in Histological Subgroups of Non-Small Cell Lung Cancer (copy number data) Refer to individual Series
2011-11-01 | E-GEOD-28582 | biostudies-arrayexpress
Project description:Using data from high-density genomic profiling arrays, we describe the profiles of somatic copy-number aberrations (SCNAs) in 486 adenocarcinomas across all three major digestive organs, including 296 gastric and esophageal cancers. This analysis revealed that although patterns of broad, chromosome arm-level alterations are similar across the three types of adenocarcinoma, focal genomic amplifications are substantially more prevalent in gastric/esophageal adenocarcinoma. A statistical analysis identified 64 regions of significantly recurrent amplification and deletion, including those shared across these tumors and those uniquely significant in adenocarcinomas from a single organ. Among significantly amplified genes are those encoding therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, events noted in 14% of colorectal adenocarcinomas and 37% of gastric/esophageal tumors suggesting that analysis of genomic amplification will be a critical source of biomarkers to guide therapies in upper gastrointestinal adenocarcinomas. While many of the other significant loci of amplifications implicate genes recognized to play roles in gastrointestinal and other cancers, other loci point to regions that may harbor novel genes contributing to these cancers. One such event is a recurrent focal deletion present in 15% of esophageal adenocarcinomas, which we narrow to a single likely target, the Runt transcription factor subunit RUNX1. Indeed, reintroduction of RUNX1 into a cell model with this deletion inhibited anchorage-independent growth. Overall, these results demonstrate genomic features common to these tumors and identify key differences that reflect distinctive biology and potential opportunities for therapeutic intervention. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from 87 cancer DNAs derived from primary tumor tissues, as well as from DNA obtained from 1,480 normal DNA samples. Signal intensities were normalized to raw copy number estimates using the tangent normalization method, as described in Beroukhim et al., In Press and Mermel et al., In preparation. The 250K Sty data from this submission were combined with data for 128 colon adenocarcinomas (Firestein et al, Nature 2008) and segmented using GLAD. These segmented data were then combined with segmented SNP 6.0 data for 62 colon, 97 gastric and 112 esophageal adenocarcinomas using common markers to anchor the segments. Data analysis across samples was performed using this GISTIC 2.0 algorithm (Mermel C et al, Genome Biology 2011).
2012-09-04 | E-GEOD-36459 | biostudies-arrayexpress
Project description:Identification of de novo copy number abnormalities arising in relapsed paediatric ALL in matched presentation and relapse samples. We identified deletions of BACH2, (BTB and CNC homology 1, basic leucine zipper transcription factor 2) at relapse. To study the role of Bach2 in pre-B ALL in a genetic experiment, we transformed pre-B cells from Bach2–/– mice with BCR-ABL1. Our findings identify Bach2 as a novel tumor suppressor upstream of p53 in pre-B ALL. 64 arrays (32 250K Nsp and 32 250K Sty) are included in this study. DNA was extracted from the presentation and relapse samples from 11 paediatric patients and DNA was extarcted from the remission samples from 10 patient and hybridised to the Affymetrix Human Mapping 500K Array Set.
2013-12-21 | E-GEOD-43060 | biostudies-arrayexpress
Project description:Primitive neuro-ectodermal tumours (PNET) of the supratentorial region are rare, highly malignant embryonal brain tumours affecting young children. Although supratentorial PNET (sPNET) are histologically similar to infratentorial PNET/medulloblastoma, sPNET have more aggressive clinical phenotypes, which suggest sPNET represents distinct biological entities. In contrast to considerable progress in understanding the signalling pathways involved in medulloblastoma, little is known about sPNET pathogenesis. Prior low resolution CGH (comparative genomic hybridization) studies indicate sPNET have frequent genomic imbalances and copy number aberrations (CNAs). To define genes involved in sPNET pathogenesis, we utilized the Affymetrix 250K Nsp SNP (single nucleotide polymorphism) analysis to identify genes targeted by recurrent CNAs in primary human sPNET samples. Copy number analysis was conducted on 39 primary PNET samples. Select target genes were validated by genomic and/or RT-PCR. Our analysis revealed frequent CNA across the sPNET genome, encompassing large and focal chromosome segments, and corroborated previous reports that isochromosome 17q, an abnormality found in ~ 30% of medulloblastoma, is rare in sPNET. Keywords: single nucleotide polymorphism array, disease state analysis A total of 56 primary sPNET samples were collected for this study from The Hospital for Sick Children, John Hopkins University, St. Jude Research Hospital, University of Cambridge, Children’s Hospital Boston, Virginia Commonwealth University, Instituto nazionale per lo studio e la cura dei tumori, and Texas Children’s Hospital, with local Institutional Research Ethics Board approval. Pineoblastoma and rhaboid tumours were specifically excluded, leaving 52 samples, 39 of which had good quality DNA available. These samples, in addition to 28 diploid reference samples (a gift from Dr. S. Scherer, University of Toronto), were analyzed on the Affymetrix GeneChip Mapping 250K Nsp SNP array. Due to sample availability at the time the arrays were run, the diploid reference samples analyzed on the Sty arrays are different from reference samples analyzed on the Nsp arrays.
2009-12-21 | E-GEOD-14087 | biostudies-arrayexpress