Oncogene
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The incidence of Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC) is increasing. Next-generation sequencing (NGS) provides an unprecedented opportunity to uncover genomic alterations during BE pathogenesis and progression to EAC, but treatment-naive surgical specimens are scarce. The objective of this study was to establish the feasibility of using widely available endoscopic mucosal biopsies for successful NGS, using samples obtained from a BE 'progressor'. ⋯ In addition, genes downstream of ARID1A that potentially contribute to the ARID1A knockdown phenotype were identified. Our studies establish the feasibility of using mucosal biopsies for NGS, which should enable the comparative analysis of larger 'progressor' versus 'non-progressor' cohorts. Further, we identify ARID1A as a novel tumor-suppressor gene in BE pathogenesis, reiterating the importance of aberrant chromatin in the metaplasia-dysplasia sequence.
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The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. ⋯ Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.
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Efficient metastasis is believed as the result of multiple genetic, epigenetic and/or post-translational events in the lifetime of a carcinoma. At the genetic level, these events may be categorized into those that occur during carcinogenesis, and those that occur during subclonal evolution. This review summarizes current knowledge of the genetics of pancreatic cancer from its initiation within a normal cell until the time that is has disseminated to distant organs, many features of which can be extrapolated to other solid tumor types. The implications of these findings to personalize genome analyses of an individual patient's tumor are also discussed.
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Aggressive variants of meningiomas (WHO grade II and III) represent up to 30% of those tumors that are among the most common primary central nervous system tumors in adults. Currently, there is no effective treatment for grade-II and -III meningiomas, the main treatment remaining surgical excision. Genetic studies have highlighted two main events associated with meningioma progression: an increase of chromosomal instability in tumors with NF2 inactivation and homozygous deletions or point mutations of the CDKN2AB locus. ⋯ In addition, we were able to detect meningiomas by using bioluminescence and to evaluate tumor vascular permeability by dynamic magnetic resonance imaging. These results show that Nf2 and Cdkn2ab cooperate to promote meningioma progression in mice. The short latency of tumor development and the ability to derive grade II/III meningioma cell cultures are key aspects of this model to promote its use in pre-clinical drug testing.
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Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). ⋯ We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.