Genomic alterations of chromosome 11 induce transcriptome dysregulation in aggressive and malignant prolactin tumours
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32191 | GEO | 2011/09/16
SECONDARY ACCESSION(S): PRJNA147405
REPOSITORIES: GEO
Similar Datasets
Project description:Pituitary tumors are generally considered as benign. However, many are invasive (45 to 55%) and some are described as aggressive with a high proliferation rate and short post-operative time to recurrence and 0.2% metastasize. The molecular events associated to the progression of the pituitary tumor toward an aggressive and malignant phenotype is still unresolved. To bring new hypothesis on signaling pathways associated to the tumor progression, we applied a wide genome analysis approach combining transcriptome analysis and CGH analysis on the same 13 prolactin tumours classified as non-invasive (n=5), invasive (n=2) and agressive-invasive tumors (n=6). In 5/6 agressive-invasive tumours a loss of a common region in the p arm of the chromosome 11 was detected. This region extending from position 14.9 to position 46.5 Mb harbours the cytobands 11p15.2, 11p15.1, 11p14.3, 11p14.2, 11p14.1, 11p13, 11p12 and 11p11.2. In 3 of these 5 tumours considered as carcinomas because of the presence of metastasis, an allelic loss is also observed in the 11q arm. The combination of data coming from genome structure exploration and transcriptomic analysis showed that allelic loss impact the expression of genes harbored in the imbalanced region. Data filtering strategy allowed us to highlight among the 139 genes harbored in the 11p region loss, 5 genes (DGKZ, CD44, TSG101, GTF2H1 and HTATIP2) that could be candidate gene for triggering the progression of prolactin tumour toward an aggressive and malignant phenotype. Finally, specific DNA alterations give one molecular argument more to consider agressive-invasive tumour and carcinomas as a distinct step in progression of the pituitary tumours.
2011-03-16 | GSE22615 | GEO
Project description:Pituitary tumors are generally considered as benign. However, many are invasive (45 to 55%) and some are described as aggressive with a high proliferation rate and short post-operative time to recurrence and 0.2% metastasize. The molecular events associated to the progression of the pituitary tumor toward an aggressive and malignant phenotype is still unresolved. To bring new hypothesis on signaling pathways associated to the tumor progression, we applied a wide genome analysis approach combining transcriptome analysis and CGH analysis on the same 13 prolactin tumours classified as non-invasive (n=5), invasive (n=2) and agressive-invasive tumors (n=6). In 5/6 agressive-invasive tumours a loss of a common region in the p arm of the chromosome 11 was detected. This region extending from position 14.9 to position 46.5 Mb harbours the cytobands 11p15.2, 11p15.1, 11p14.3, 11p14.2, 11p14.1, 11p13, 11p12 and 11p11.2. In 3 of these 5 tumours considered as carcinomas because of the presence of metastasis, an allelic loss is also observed in the 11q arm. The combination of data coming from genome structure exploration and transcriptomic analysis showed that allelic loss impact the expression of genes harbored in the imbalanced region. Data filtering strategy allowed us to highlight among the 139 genes harbored in the 11p region loss, 5 genes (DGKZ, CD44, TSG101, GTF2H1 and HTATIP2) that could be candidate gene for triggering the progression of prolactin tumour toward an aggressive and malignant phenotype. Finally, specific DNA alterations give one molecular argument more to consider agressive-invasive tumour and carcinomas as a distinct step in progression of the pituitary tumours. Copy number analysis of Affymetrix Genome-Wide Human SNP Array 6.0 was performed for 13 prolactin tumors, 6 aggressive-invasive, 2 invasive, 5 non-invasive. The same analysis was performed for one normal pituitary and one genomic DNA called "reference 103" from Affymetrix.
2011-03-16 | E-GEOD-22615 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE22615: Genomic alterations of chromosome 11 induce transcriptomic dysregulation in aggressive and malignant prolactin tumours GSE22812: Transcriptomic dysregulation in aggressive and malignant prolactin tumours Refer to individual Series
2011-09-15 | E-GEOD-32191 | biostudies-arrayexpress
Project description:Pituitary tumours are generally benign. However, many are invasive and some of these are aggressive with high proliferation and recurrence rates. Only metastatic tumours are considered malignant and are rare (0.2%). To identify molecular events associated with the aggressive and malignant phenotypes, we combined a comparative genomic hybridization and transcriptomic analysis of 13 prolactin (PRL) tumours classified as non-invasive (NI; n=5), invasive (I; n=2) or aggressive-invasive (AI; n=6). Each tumour showed copy number alterations which appeared to be varied and discrete in the NI and I tumour groups, and more numerous and extensive in the AI tumour group. Allelic loss within the p arm region of chromosome 11 was detected in five of the AI tumours. This region contains the cytobands 11p15.2, 11p15.1, 11p14.3, 11p14.2, 11p14.1, 11p13, 11p12 and 11p11.2. Furthermore, an allelic loss in the 11q arm was also observed in three of these five tumours, which were considered malignant based on the presence of metastases. The comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. An original data filtering strategy allowed us to highlight five genes (DGKZ, CD44, TSG101, GTF2H1 and HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumours. Our novel combined genomic and transcriptomic analysis underlines the importance of chromosome 11 allelic loss in aggressive and malignant PRL tumours and led us to propose a new strategy to find markers of progression in rare tumours.
2011-03-16 | GSE22812 | GEO
Project description:Pituitary tumours are generally benign. However, many are invasive and some of these are aggressive with high proliferation and recurrence rates. Only metastatic tumours are considered malignant and are rare (0.2%). To identify molecular events associated with the aggressive and malignant phenotypes, we combined a comparative genomic hybridization and transcriptomic analysis of 13 prolactin (PRL) tumours classified as non-invasive (NI; n=5), invasive (I; n=2) or aggressive-invasive (AI; n=6). Each tumour showed copy number alterations which appeared to be varied and discrete in the NI and I tumour groups, and more numerous and extensive in the AI tumour group. Allelic loss within the p arm region of chromosome 11 was detected in five of the AI tumours. This region contains the cytobands 11p15.2, 11p15.1, 11p14.3, 11p14.2, 11p14.1, 11p13, 11p12 and 11p11.2. Furthermore, an allelic loss in the 11q arm was also observed in three of these five tumours, which were considered malignant based on the presence of metastases. The comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. An original data filtering strategy allowed us to highlight five genes (DGKZ, CD44, TSG101, GTF2H1 and HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumours. Our novel combined genomic and transcriptomic analysis underlines the importance of chromosome 11 allelic loss in aggressive and malignant PRL tumours and led us to propose a new strategy to find markers of progression in rare tumours. Transcriptomic analysis of Codelink Human Whole Genome Bioarray was performed for 13 prolactin tumors: 6 aggressive-invasive, 2 invasive, and 5 non-invasive.
2011-03-16 | E-GEOD-22812 | biostudies-arrayexpress
Project description:Wilms' tumour is one of the most common solid tumours of childhood. 11p13 (WT1 locus) and 11p15.5 (WT2 locus) are known to have genetic or epigenetic aberrations in these tumours. In Wilms' tumours, mutation of the Wilms tumour 1 (WT1) gene at the WT1 locus has been reported, and the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1, can undergo maternal deletion or alterations associated with imprinting. Although these alterations have been identified in many studies, it is still not clear how frequently combined genetic and epigenetic alterations of these loci are involved in Wilms' tumours or how these alterations occur. To answer both questions, we performed genetic and epigenetic analyses of these loci, together with an additional gene, CTNNB1, in 35 sporadic Wilms' tumours. Loss of heterozygosity of 11p15.5 and loss of imprinting of IGF2 were the most frequent genetic (29%) and epigenetic (40%) alterations in Wilms' tumours, respectively. In total, 83% of the tumours had at least one alteration at 11p15.5 and/or 11p13. One-third of the tumours had alterations at multiple loci. Our results suggest that chromosome 11p is not only genetically but also epigenetically critical for the majority of Wilms' tumours.
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Project description:Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.
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Project description:The complex phenotypic and genetic nature of anxieties hampers progress in unravelling their molecular etiologies. Dogs present extensive natural variation in fear and anxiety behaviour and could advance the understanding of the molecular background of behaviour due to their unique breeding history and genetic architecture. As dogs live as part of human families under constant care and monitoring, information from their behaviour and experiences are easily available. Here we have studied the genetic background of fearfulness in the Great Dane breed. Dogs were scored and categorised into cases and controls based on the results of the validated owner-completed behavioural survey. A genome-wide association study in a cohort of 124 dogs with and without socialisation as a covariate revealed a genome-wide significant locus on chromosome 11. Whole exome sequencing and whole genome sequencing revealed extensive regions of opposite homozygosity in the same locus on chromosome 11 between the cases and controls with interesting neuronal candidate genes such as MAPK9/JNK2, a known hippocampal regulator of anxiety. Further characterisation of the identified locus will pave the way for molecular understanding of fear in dogs and may provide a natural animal model for human anxieties.
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Project description:Prolactin is essential for normal mammary gland development and differentiation, and has been shown to promote tumor cell proliferation and chemotherapeutic resistance. Soluble isoforms of the prolactin receptor (PrlR) have been reported to regulate prolactin bioavailability by functioning as 'prolactin-binding proteins'. Included in this category is ?7/11, a product of alternate splicing of the PrlR primary transcript. However, the direct interactions of prolactin with ?7/11, and the resulting effect on cell behavior, have not been investigated. Herein, we demonstrate the ability of ?7/11 to bind prolactin using a novel proximity ligation assay and traditional immunoprecipitation techniques. Biochemical analyses demonstrated that ?7/11 was heavily glycosylated, similar to the extracellular domain of the primary PrlR, and that glycosylation regulated the cellular localization and secretion of ?7/11. Low levels of ?7/11 were detected in serum samples of healthy volunteers, but were undetectable in human milk samples. Expression of ?7/11 was also detected in six of the 62 primary breast tumor biopsies analyzed; however, no correlation was found with ?7/11 expression and tumor histotype or other patient demographics. Functional analysis demonstrated the ability of ?7/11 to inhibit prolactin-induced cell proliferation as well as alter prolactin-induced rescue of cell cycle arrest/early senescence events in breast epithelial cells. Collectively, these data demonstrate that ?7/11 is a novel regulatory mechanism of prolactin bioavailability and signaling.
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