The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. Additionally, 373 tumors were assayed for copy number alterations via Agilent 244A CGH arrays and 153 breast, lung, and colon samples were assayed for mRNA abundance with Affymetrix HuEx1 Exon Arrays.
Diverse somatic mutation patterns and pathway alterations in human cancers.
Specimen part
View SamplesFor this study we selected a gene, -synuclein (SNCA), that is consistently under-expressed in MCF7 cells and breast tumors. Following transfection with an SNCA expression construct, two stable MCF7 clones (named MCF7-SNCA #1 and 2) were selected and examined for expression differences relative to the parental MCF7 cells.
Cancer develops, progresses and responds to therapies through restricted perturbation of the protein-protein interaction network.
Specimen part, Cell line
View SamplesEndocrine therapies targeting the proliferative effect of 17-estradiol (17E2) through estrogen receptor (ER) are the most effective systemic treatment of ER-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through a molecular mechanism that is not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors (AIs) in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ER. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were influenced by transcription factors known to be involved in acquired resistance or cell proliferation (e.g. IRF1 and E2F1, respectively) but, notably, not by canonical ER transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ER were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ER-negative status, early response to letrozole and recurrence after tamoxifen treatment. This study proposes a mechanism for acquired resistance to estrogen deprivation that is coordinated across biological levels and independent of canonical ER function.
Biological reprogramming in acquired resistance to endocrine therapy of breast cancer.
Specimen part, Cell line
View SamplesIn the current study, we have performed a gene expression analysis of well characterized and defined populations of human adipose-derived stem cells (hASCs) before and after in vitro induction of osteogenic and myogenic differentiation that allows identifying DNA methylation- regulated differentiation genes. We have also address the extent of the epigenetic programming of hASCs- derived differentiated cells by comparing the expression profiling of these cells with their somatic counterparts from primary tissues. Finally, we also compared the patterns of expression of hASCs (and their derivatives)
DNA methylation plasticity of human adipose-derived stem cells in lineage commitment.
Specimen part
View SamplesBackground: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available.
Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.
Disease
View SamplesIn March 2006, murine Bone Marrow Stromal Cells (BMSC) were flown in the Soyuz 12S to the International Space Station to investigate the effects of microgravity on their osteogenic potential in a three-dimensional environment. BMSC were grown in porous bioceramic Skelite disks ( 9 mm x T 1.2 mm). The constructs were exposed to microgravity for ca. 8 days, then fixed for RNA extraction. While the flight experiment was performed in fully automated hardware inside the KUBIK incubator, one group of control samples were incubated inside manually operated hardwares (flight control), and the other control group was incubated under routine laboratory conditions (lab control). The altered gene expression profile was analyzed by Mouse Gene 1.0 ST array (Affymetrix) representing whole-transcript coverage. Each one of the 28853 genes is represented on the array by approximately 26 probes spread across the full length of the gene, providing a more complete and more accurate picture of gene expression than the 3 based expression array design.
Activation of nervous system development genes in bone marrow derived mesenchymal stem cells following spaceflight exposure.
Specimen part, Disease
View SamplesActinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood.
Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel.
Specimen part, Disease, Disease stage, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Transcriptome and cytogenetic profiling analysis of matched in situ/invasive cutaneous squamous cell carcinomas from immunocompetent patients.
Sex, Age, Specimen part, Disease stage, Subject
View SamplesAlthough most cutaneous squamous cell carcinomas (cSCC) develop from actinic keratoses (AK), the key events for this evolution remain unclear. We have combined the results of different genomic and expression array platforms on matched samples of sun-exposed skin, AK and cSCC from ten immunocompetent patients, with the objective of better understanding the mechanisms involved in this progression. Gene expression analysis and copy number alterations were assessed using GeneChip Human Gene 2.0 ST Array (Affymetrix) and CytoScan HD Cytogenetics Solution (Affymetrix) platforms, respectively. Integration of genome and transcriptome results was evaluated using the DR-Integrator tool. Additional studies (qPCR, immunohistochemistry and Western blot) were performed for selected genes. Twenty-two genes showed a progressive expression spectrum from clinically normal sun-exposed skin samples to cSCC. FOSL1 and BNC1 encode transcription factors whose expression was increased in cSCC in the expression array and the qPCR. By immunohistochemistry, FOSL1 showed an intense staining at the invasive front of cSCC samples and BNC1 expression varied from a nuclear location (sun-exposed skin) to a cytoplasmic location (cSCC). Western blot analyses confirmed the enhancement of FOSL1 and BNC1 expression. Additionally, the smallest overlapping regions of genomic imbalance (SORIs) involving at least 3 of the samples of each group (sun-exposed skin, AK or cSCC) were selected. One of the SORIs was a deletion in the p24.1 band of chromosome 3, shared by 7 of the cSCC. A strong correlation in the integration analysis was found for NEK10, a gene contained in the previously mentioned SORI. Loss of NEK10 expression in cSCC was confirmed by immunohistochemistry and western blot analyses. In conclusion, our findings suggest that FOSL1 may play a role in promoting the cSCC invasion ability. We have also identified two additional genes, NEK10 and BNC1, which could also act as tumor drivers.
Transcriptome and cytogenetic profiling analysis of matched in situ/invasive cutaneous squamous cell carcinomas from immunocompetent patients.
Sex, Age, Specimen part, Disease stage, Subject
View SamplesAnalysis of the expression profiles of MCF7 cells transduced with a control shRNA and an TSC2-targeted shRNA (leading to tuberin depletion).
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.
Cell line
View Samples