Dataset Information

Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors.

ABSTRACT: Integrative genomics approaches associating DNA structure and transcriptomic analysis should allow the identification of cascades of events relating to tumor aggressiveness. While different genome alterations have been identified in pituitary tumors, none have ever been correlated with the aggressiveness. This study focused on one subtype of pituitary tumor, the prolactin (PRL) pituitary tumors, to identify molecular events associated with the aggressive and malignant phenotypes. We combined a comparative genomic hybridization and transcriptomic analysis of 13 PRL tumors classified as nonaggressive or aggressive. Allelic loss within the p arm region of chromosome 11 was detected in five of the aggressive tumors. Allelic loss in the 11q arm was observed in three of these five tumors, all three of which were considered as malignant based on the occurrence of metastases. Comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. Data filtering allowed us to highlight five deregulated genes (DGKZ, CD44, TSG101, GTF2H1, HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumors. Our combined genomic and transcriptomic analysis underlines the importance of chromosome allelic loss in determining the aggressiveness and malignancy of tumors.

SUBMITTER: Wierinckx A

PROVIDER: S-EPMC8094244 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors.

Wierinckx Anne A Roche Magali M Raverot Gérald G Legras-Lachuer Catherine C Croze Séverine S Nazaret Nicolas N Rey Catherine C Auger Carole C Jouanneau Emmanuel E Chanson Philippe P Trouillas Jacqueline J Lachuer Joël J

Brain pathology (Zurich, Switzerland) 20110223 5

Integrative genomics approaches associating DNA structure and transcriptomic analysis should allow the identification of cascades of events relating to tumor aggressiveness. While different genome alterations have been identified in pituitary tumors, none have ever been correlated with the aggressiveness. This study focused on one subtype of pituitary tumor, the prolactin (PRL) pituitary tumors, to identify molecular events associated with the aggressive and malignant phenotypes. We combined a c ...[more]

PMID: 21251114

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Project description:Pituitary neuroendocrine tumors (PitNETs) are the most common pituitary tumors and the second most common brain tumors. Although the vast majority (>90%) are benign, a small percentage (<2%) are aggressive. These aggressive PitNETs (AgPitNETs) are defined by the presence of radiological invasion, a high rate of cell proliferation, resistance to conventional treatments, and/or a high propensity for recurrence. Lastly, there are the rare pituitary carcinomas, also known as metastatic PitNETs (MetPitNETs), which account for only 0.2% of cases and are defined by the presence of craniospinal or distant metastases. At present, there are no definitive factors that allow us to predict with certainty the aggressive behavior of PitNETs, making the therapeutic management of AgPitNETs a real challenge. Surgery is considered the first-line treatment for AgPitNETs and MetPitNETs. Radiation therapy can be effective in controlling tumor growth and regulating hormone hypersecretion. Currently, there are no approved non-endocrine medical therapies for the management of AgPitNETs/MetPitNETs, mainly due to the lack of randomized controlled clinical trials. As a result, many of the medical therapies used are off-label drugs, and several are under investigation. Temozolomide (TMZ) is now recognized as the primary medical treatment following the failure of standard therapy (medical treatment, surgery, and radiotherapy) in AgPitNETs/MetPitNETs due to its ability to improve overall and progression-free survival rates in responding patients over 5 years. Other therapeutic options include pituitary-targeted therapies (dopamine agonists and somatostatin analogs), hormonal antisecretory drugs, non-hormonal targeted therapies, radionuclide treatments, and immunotherapy. However, the number of patients who have undergone these treatments is limited, and the results obtained to date have been inconsistent. As a result, it is imperative to expand the cohort of patients undergoing treatment to better determine the therapeutic efficacy and safety of these drugs for individuals with AgPitNETs/MetPitNETs.

Project description:PurposeMyopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia.MethodsIndividuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed.ResultsSingle variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13.ConclusionsWe identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

Dataset Information

Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors.

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Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors.

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