Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1000753 | ENA |
REPOSITORIES: ENA
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Project description:Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier) combined with spindle cell hemangiomas (Maffucci). We found somatic heterozygous IDH1 mutations (R132C and R132H) in 83% of enchondromas, benign cartilage tumors, as well as in 40% of spindle cell hemangiomas, benign vascular lesions. In total, 33 of 42 (78%) patients with Ollier disease and 7 of 13 (54%) patients with Maffucci syndrome carried a mutation in at least one of their tumors. Twelve patients with multiple tumors at different locations displayed identical mutations in separate lesions. Immunohistochemical staining for the R132H IDH1 mutant protein suggested intraneoplastic as well as somatic mosaicism. IDH1 mutations were less frequent (63%) in high grade malignant cartilage tumors in Ollier disease, suggesting that IDH1 is less important for malignant transformation. IDH1 and IDH2 mutations were found in 36% of sporadic cartilage tumors and in four cell lines derived from sporadic chondrosarcomas. 16 samples were analyzed in two color experiment, using normal male or female as a reference sample (gender mismatched)
2011-11-05 | E-GEOD-30354 | biostudies-arrayexpress
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies.
2011-08-02 | GSE27691 | GEO
Project description:Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase (PI3K) and are among the commonest somatic mutations in cancer and mosaic, developmental overgrowth disorders. We recently demonstrated that the ‘hotspot’ variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human induced pluripotent stem cells (iPSCs), and moreover demonstrated multiple oncogenic PIK3CA copies in a substantial subset of human cancers. To identify the molecular mechanism underpinning PIK3CAH1047R allele dose-dependent stemness, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). PIK3CAH1047R/H1047R iPSCs exhibited altered expression of 5644 genes and 248 proteins, whereas heterozygous hPSCs showed 492 and 54 differentially-expressed genes and proteins, respectively, confirming a nearly deterministic phenotypic effect of homozygosity for PIK3CAH1047R. Pathway and network-based analyses predicted a strong association between self-sustained TGFb/NODAL signaling and the ‘locked’ stemness phenotype induced by homozygosity for PIK3CAH1047R. This stemness gene signature was maintained without exogenous NODAL in PIK3CAH1047R/H1047R iPSCs and was reversed by pharmacological inhibition of TGFb/NODAL signaling but not by PIK3CA-specific inhibition. Analysis of PIK3CA-associated human breast cancers revealed increased expression of the stemness markers NODAL and POU5F1 as a function of disease stage and PIK3CAH1047R allele dosage. Together with emerging realization of the link between NODAL re-expression and aggressive cancer behavior, our data suggest that TGFb/NODAL inhibitors warrant testing in advanced breast tumors with multiple oncogenic PIK3CA copies.
2021-03-03 | PXD014719 | Pride
Project description:Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier) combined with spindle cell hemangiomas (Maffucci). We found somatic heterozygous IDH1 mutations (R132C and R132H) in 83% of enchondromas, benign cartilage tumors, as well as in 40% of spindle cell hemangiomas, benign vascular lesions. In total, 33 of 42 (78%) patients with Ollier disease and 7 of 13 (54%) patients with Maffucci syndrome carried a mutation in at least one of their tumors. Twelve patients with multiple tumors at different locations displayed identical mutations in separate lesions. Immunohistochemical staining for the R132H IDH1 mutant protein suggested intraneoplastic as well as somatic mosaicism. IDH1 mutations were less frequent (63%) in high grade malignant cartilage tumors in Ollier disease, suggesting that IDH1 is less important for malignant transformation. IDH1 and IDH2 mutations were found in 36% of sporadic cartilage tumors and in four cell lines derived from sporadic chondrosarcomas.
2011-11-05 | GSE30354 | GEO
Project description:Purpose: Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular malformations that may lead to stroke, seizures and other clinical sequelae. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. In our previous research, we’ve shown that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. The overall goal of this study was to identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). We also analyzed the plasma miRNome of patients with (1) DVA without associated CCM, as well as (2) DVA with an associated CCM) to identify circulating miRNAs that might serve as biomarkers reflecting PIK3CA activity. Methods: We collected and sequenced the plasma miRNome of 12 individuals with a sporadic CCM associated with a DVA (CCM + DVA), 6 individuals with a DVA without a CCM (DVA only), and 7 healthy controls. Results: We found that the identical PIK3CA mutation is found in endothelial cells of both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. The analyses miR-134-5p was downregulated in the groups of patients with only a DVA only group (when compared to healthy controls). This miRNA has been shown to target PIK3CA. In addition, miR-182-5p, was upregulated and targets MAP3K3; while let-7c-5p was downregulated and targets both PIK3CA and MAP3K3 in the group of patients with CCM and an associated DVA (when compared to DVA only). Conclusions: These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.
2022-02-06 | GSE195732 | GEO
Project description:Objectives: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved. Material and methods: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n=243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n=62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n=91). Results: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors. Conclusions: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.
2018-04-02 | GSE95805 | GEO
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies. Affymetrix SNP array analysis was performed with Mouse Diversity Genotyping Arrays (Affymetrix) on genomic DNA extracted from frozen biopsies of 6 recurrent mouse mammary tumor samples. Copy number analysis was performed for the mouse mammary tumors using genomic DNA from normal mammary tissue as the reference for copy number inference.
2011-08-01 | E-GEOD-27691 | biostudies-arrayexpress
Project description:PI3K/AKT pathway plays one of pivotal roles in breast cancer development and maintenance. PIK3CA, coding PIK3 catalytic subunit, is the oncogene which shows the high frequency of gain-of-function mutations leading to the PI3K/AKT pathway activation in breast cancer. In particular in the ERα-positive breast tumors PIK3CA mutations have been observed in 30% to 40%. However, genes expressed in connection to the pathway activation in breast tumorigenesis remain largely unknown. To identify downstream relevant target genes (and signaling pathways) turned on by the aberrant PI3K/AKT signal in breast tumors, we analyzed gene expression by pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations. 43 ERα-positive breast tumors including 14 tumors with PIK3CA mutations and 29 tumors without PIK3CA mutattions were used as screening set for microarray.
2011-01-10 | E-GEOD-22035 | biostudies-arrayexpress
Project description:Multiple family members with cancer or individuals with multiple primary cancers are indicative of potential genetic etiology1. Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS)2. We identified a TP53 tetramerization domain (TD) missense mutation c.1000G>C;p.G334R, in a family with LFS-associated cancers. Twenty-one additional probands were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited haplotype. While classical p53 target gene activation was maintained in p.G334R mutant cell lines treated with Nutlin-3a, a subset of p53 target genes, including PCLO, PLTP, PLXNB3 and LCN15, showed defective transactivation. Structural analysis demonstrated thermal instability of the mutant TD, and the G334R mutant protein showed increased preponderance of mutant conformation protein. TP53 c.1000G>C;p.G334R is a rare AJ-predominant mutation associated with low penetrance Li-Fraumeni Syndrome
2020-07-24 | GSE143741 | GEO
Project description:Ollier disease and Maffucci syndrome are non-hereditary skeletal disorderscharacterized by multiple enchondromas (Ollier disease) combined with spindle cellhemangiomas (Maffucci syndrome). Somatic heterozygous IDH1 (R132C and R132H) orIDH2 (R172S) mutations were found in 87% of enchondromas, benign cartilage tumors,as well as in 70% of spindle cell hemangiomas, benign vascular lesions. In total, 35 of 43(81%) patients with Ollier disease and 10 of 13 (77%) patients with Maffucci syndromecarried IDH1 (98%) or rarely IDH2 (2%) mutations in their tumors. Fourteen patientswith multiple tumors at different anatomic locations displayed identical mutations inseparate lesions. Since in other tumor types the presence of an IDH1 mutation is strongly associated withhypermethylation 26, 27, we assessed whether there was a difference in methylation patternof enchondromas with (n = 8) and without (n = 4) IDH1 mutations detactable at Sangersequencing. Methylation and expressionprofiling showed that IDH1 mutations in cartilage tumors are associated withhypermethylation and downregulation of the expression of several genes.
2011-11-05 | GSE31337 | GEO