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The molecular genetic profile of neuroblastoma

Diagnostic Histopathology 2014年第2期20卷 76-83页

作者： Thorner, Paul Scott Division of Pathology Hospital for Sick Children Toronto Canada Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Canada

Neuroblastoma is the most common extracranial solid tumour of childhood and is characterized by a remarkable heterogeneity in histology and molecular biology that is reflected in its clinical outcome. Unlike many paediatric malignancies, molecular genetic results are used for prognosis rather than diagnosis. The molecular genetic changes in neuroblastoma are reviewed and summarized. Some genetic changes (ploidy, MYCN copy number, 11q deletion) are used for risk stratification that determines patient treatment. Other genetic changes (e.g 1p deletion, 17q gain) are strong prognostic indicators for an unfavourable outcome. Mutations in individual genes (e.g ALK) are becoming important in personalizing therapy as more agents become available for 'druggable' targets. Newer genetic data related to miRNA expression and genome-wide association screening offer the promise of new avenues to pursue to improve the dismal outcome in high risk patients with neuroblastoma. © 2014 Elsevier Ltd.

关键词： 17q 1p ALK ATRX expression array Genomic array MiRNA MYCN Neuroblastoma Ploidy

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Multi-platform genome-wide analysis of melanoma progression to brain metastasis

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GENOMICS DATA 2014年 2卷 150-152页

作者： Marzese, Diego M. Huynh, Jamie L. Kawas, Neal P. Hoon, Dave S. B. JWCI Providence St Johns Hlth Ctr Dept Mol Oncol Santa Monica CA 90404 USA

Melanoma has a high tendency to metastasize to brain tissue. The understanding about the molecular alterations of early-stage melanoma progression to brain metastasis (MBM) is very limited. Identifying MBM-specific genomic and epigenomic alterations is a key initial step in understanding its aggressive nature and identifying specific novel druggable targets. Here, we describe a multi-platform dataset generated with different stages of melanoma progression to MBM. This data includes genome-wide DNA methylation (Illumina HM450K BeadChip), gene expression (Affymetrix HuEx 1.0 ST array), single nucleotide polymorphisms (SNPs) and copy number variation (CNV;Affymetrix SNP 6.0 array) analyses of melanocyte cells (MNCs), primary melanoma tumors (PRMs), lymph node metastases (LNMs) and MBMs. The analysis of this data has been reported in our recently published study (Marzese et al., 2014). (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

关键词： Melanoma Brain metastasis Cancer progression HM450K expression array SNP array

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Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines

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BMC GENOMICS 2014年第1期15卷 1-22页

作者： Li, Liang Fridley, Brooke L. Kalari, Krishna Niu, Nifang Jenkins, Gregory Batzler, Anthony Abo, Ryan P. Schaid, Daniel Wang, Liewei Mayo Clin Dept Mol Pharmacol & Expt Therapeut Div Clin Pharmacol Rochester MN USA Mayo Clin Dept Hlth Sci Res Div Biomed Stat & Informat Rochester MN 55905 USA

Background: Two cytidine analogues, gemcitabine and cytosine arabinoside (AraC), are widely used in the treatment of a variety of cancers with a large individual variation in response. To identify potential genetic biomarkers associated with response to these two drugs, we used a human lymphoblastoid cell line (LCL) model system with extensive genomic data, including 1.3 million SNPs and 54,000 basal expression probesets to perform genome-wide association studies (GWAS) with gemcitabine and AraC IC50 values. Results: We identified 11 and 27 SNP loci significantly associated with gemcitabine and AraC IC50 values, respectively. Eleven candidate genes were functionally validated using siRNA knockdown approach in multiple cancer cell lines. We also characterized the potential mechanisms of genes by determining their influence on the activity of 10 cancer-related signaling pathways using reporter gene assays. Most SNPs regulated gene expression in a trans manner, except 7 SNPs in the PIGB gene that were significantly associated with both the expression of PIGB and gemcitabine cytotoxicity. Conclusion: These results suggest that genetic variation might contribute to drug response via either cis- or trans- regulation of gene expression. GWAS analysis followed by functional pharmacogenomics studies might help identify novel biomarkers contributing to variation in response to these two drugs and enhance our understanding of underlying mechanisms of drug action.

关键词： Cytidine analogues Gemcitabine Cytosine arabinoside Lymphoblastoid cell lines expression array Genome-wide SNPs Genome-wide association study Functional genomics Translational research

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Neurodevelopmental alcohol exposure elicits long-term changes to gene expression that alter distinct molecular pathways dependent on timing of exposure

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JOURNAL OF NEURODEVELOPMENTAL DISORDERS 2013年第1期5卷 1-19页

作者： Kleiber, Morgan L. Mantha, Katarzyna Stringer, Randa L. Singh, Shiva M. Univ Western Ontario Dept Biol Mol Genet Unit London ON N6A 5B7 Canada

Background: Maternal alcohol consumption is known to adversely affect fetal neurodevelopment. While it is known that alcohol dose and timing play a role in the cognitive and behavioral changes associated with prenatal alcohol exposure, it is unclear what developmental processes are disrupted that may lead to these phenotypes. Methods: Mice (n=6 per treatment per developmental time) were exposed to two acute doses of alcohol (5 g/kg) at neurodevelopmental times representing the human first, second, or third trimester equivalent. Mice were reared to adulthood and changes to their adult brain transcriptome were assessed using expression arrays. These were then categorized based on Gene Ontology annotations, canonical pathway associations, and relationships to interacting molecules. Results: The results suggest that ethanol disrupts biological processes that are actively occurring at the time of exposure. These include cell proliferation during trimester one, cell migration and differentiation during trimester two, and cellular communication and neurotransmission during trimester three. Further, although ethanol altered a distinct set of genes depending on developmental timing, many of these show interrelatedness and can be associated with one another via 'hub' molecules and pathways such as those related to huntingtin and brain-derived neurotrophic factor. Conclusions: These changes to brain gene expression represent a 'molecular footprint' of neurodevelopmental alcohol exposure that is long-lasting and correlates with active processes disrupted at the time of exposure. This study provides further support that there is no neurodevelopmental time when alcohol cannot adversely affect the developing brain.

关键词： Fetal alcohol spectrum disorders Development Brain Mouse Gene expression expression array

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Deciphering gene expression program of MAP3K1 in mouse eyelid morphogenesis

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DEVELOPMENTAL BIOLOGY 2013年第1期374卷 96-107页

作者： Jin, Chang Chen, Jing Meng, Qinghang Carreira, Vinicius Tam, Neville N. C. Geh, Esmond Karyala, Saikumar Ho, Shuk-Mei Zhou, Xiangtian Medvedovic, Mario Xia, Ying Univ Cincinnati Coll Med Dept Environm Hlth Kettering Lab Cincinnati OH 45267 USA Wenzhou Med Coll Sch Optometry & Ophthalmol Wenzhou Peoples R China Wenzhou Med Coll Hosp Eye Wenzhou Peoples R China

Embryonic eyelid closure involves forward movement and ultimate fusion of the upper and lower eyelids, an essential step of mammalian ocular surface development. Although its underlying mechanism of action is not fully understood, a functional mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is required for eyelid closure. Here we investigate the molecular signatures of MAP3K1 in eyelid morphogenesis. At mouse gestational day E15.5, the developmental stage immediately prior to eyelid closure, MAP3K1 expression is predominant in the eyelid leading edge (LE) and the inner eyelid (IE) epithelium. We used laser capture microdissection (LCM) to obtain highly enriched LE and IE cells from wild type and MAP3K1-deficient fetuses and analyzed genome-wide expression profiles. The gene expression data led to the identification of three distinct developmental features of MAP3K1. First, MAP3K1 modulated Wnt and Sonic hedgehog signals, actin reorganization, and proliferation only in LE but not in IE epithelium, illustrating the temporal-spatial specificity of MAP3K1 in embryogenesis. Second, MAP3K1 potentiated AP-2 alpha expression and SRF and AP-1 activity, but its target genes were enriched for binding motifs of AP-2 alpha and SRF, and not AP-1, suggesting the existence of novel MAP3K1-AP-2 alpha/SRF modules in gene regulation. Third, MAP3K1 displayed variable effects on expression of lineage specific genes in the LE and 1E epithelium, revealing potential roles of MAP3K1 in differentiation and lineage specification. Using LCM and expression array, our studies have uncovered novel molecular signatures of MAP3K1 in embryonic eyelid closure. (C) 2012 Elsevier Inc. All rights reserved.

关键词： Laser capture microdissection expression array Embryonic eyelid closure Signaling pathways

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Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters

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EXPERIMENTAL DERMATOLOGY 2013年第7期22卷 494-496页

作者： Anton Puig-Butille, Joan Malvehy, Josep Potrony, Miriam Trullas, Carles Garcia-Garcia, Francisco Dopazo, Joaquin Puig, Susana Hosp Clin Barcelona IDIBAPS Melanoma Unit Biochem & Mol Genet Serv E-08036 Barcelona Spain Inst Salud Carlos III CIBER Enfermedades Raras Barcelona Spain Hosp Clin Barcelona IDIBAPS Dept Dermatol Melanoma Unit E-08036 Barcelona Spain ISDIN Barcelona Spain Ctr Invest Principe Felipe Dept Bioinformat Valencia Spain CIPF Natl Inst Bioinformat Valencia Spain CIBERER Valencia Spain

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P=0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P=0.012) and IL-1B (P=0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

关键词： actinic keratoses CPI-17 cutaneous field of cancerization expression array PPP1R14A

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expression signature in peripheral blood cells for molecular diagnosis of head and neck squamous cell carcinoma

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ORAL DISEASES 2013年第5期19卷 452-455页

作者： Braakhuis, B. J. M. Graveland, A. P. Dijk, F. Ylstra, B. van Wieringen, W. N. Leemans, C. R. Brakenhoff, R. H. Vrije Univ Amsterdam Med Ctr Dept Otolaryngol & Head Neck Surg Amsterdam Netherlands Vrije Univ Amsterdam Med Ctr Dept Pathol Microarray Core Facil Amsterdam Netherlands Vrije Univ Amsterdam Med Ctr Dept Epidemiol & Biostat Amsterdam Netherlands Vrije Univ Amsterdam Dept Math Amsterdam Netherlands

Patients with head and neck squamous cell carcinoma (HNSCC) have a poor prognosis due to the development of locoregional recurrences, distant metastases, and second primary tumors. There is an urgent need for biomarkers that enable detection and monitoring of the disease to provide adequate therapeutic strategies. In this study, we have investigated markers in peripheral blood cells (PBC) of 28 HNSCC patients who underwent surgery by means of expression profiling. Our hypothesis is that nucleated blood cells circulate continuously, also pass the tumor, and change their expression profile in response to tumor cell factors. For comparison, we enrolled a control group of 11 patients who underwent surgery in the head and neck region for non-HNSCC reasons. A set of 2949 genes was found to be statistically different between the groups (P < 0.05, false discovery rate-corrected) and the most prominently different pathways were EIF2, EIF4, and mTOR signaling. These preliminary results are promising and warrant further studies on the definitive role of PBC gene expression as a biomarker for HNSCC detection and monitoring.

关键词： biological marker expression array head and neck cancer oral cancer peripheral blood cell squamous cell carcinoma

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Genomic approach towards personalized anticancer drug therapy

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PHARMACOGENOMICS 2012年第2期13卷 191-199页

作者： Midorikawa, Yutaka Tsuji, Shingo Takayama, Tadatoshi Aburatani, Hiroyuki Univ Tokyo Adv Sci & Technol Res Ctr Genome Sci Div Meguro Ku Tokyo 1538904 Japan Nihon Univ Sch Med Dept Digest Surg Itabashi Ku Tokyo 1738610 Japan

Stratification of patients for multidrug response is a promising strategy for cancer treatment. Genome-based prediction models have great potential for this purpose because the extent of drug sensitivity may be attributed to the heterogeneity of the underlying genetic characteristics of cancer. However, microarray data is difficult to analyze and is not reproducible. Several machine-learning algorithms have therefore been developed in a repeatable manner. Random forests algorithm, which uses an ensemble approach based on classification and regression trees, appears to be superior for predicting multidrug sensitivity. This is because ensemble methods are more effective when there are much more predictors than samples. Here, we review recent advances in the development of classification algorithms using microarray technology for prediction of anticancer sensitivity, discuss the availability of ensemble methods for prediction models, and present data regarding the identification of potential responders to FOLFOX therapy using random forests algorithm.

关键词： anticancer therapy ensemble method expression array machine-learning algorithm personalized therapy predictor genes

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Identification of the a kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma

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JOURNAL OF SURGICAL ONCOLOGY 2012年第4期105卷 381-386页

作者： Hayashi, M. Nomoto, S. Kanda, M. Okamura, Y. Nishikawa, Y. Yamada, S. Fujii, T. Sugimoto, H. Takeda, S. Kodera, Y. Nagoya Univ Dept Surg 2 Grad Sch Med Showa Ku Nagoya Aichi 4668550 Japan

Background: Hepatocellular carcinoma (HCC) is a major health problem, and identification of new tumor-related genes is an urgent task. Methods: To detect tumor-related genes effectively, we performed double-combination array analysis, which consisted of an expression array and a single nucleotide polymorphism (SNP) array of a single surgical HCC specimen. Results: expression array analysis identified AKAP12 as one of the genes with reduced expression in HCC tissues when compared with non-cancerous adjacent hepatic tissues. In addition, AKAP12 expression levels in tumor tissues from 48 HCC samples were significantly lower (P < 0.001) than those in normal tissues, and the downregulation was significantly correlated with poor overall survival rate (P = 0.003). However, SNP array analysis revealed that locus 6q24-q25 where AKAP12 was located did not show chromosomal deletion. In contrast, hypermethylation in the AKAP12 promoter regions was observed in 41 of 48 HCC samples. We then confirmed that AKAP12 gene re-expression occurs after 5-aza-2'-deoxycytidine (5-aza-dC) treatment through direct sequence analysis of the AKAP12 promoter region in HCC cell lines. Conclusions: The current data suggest that AKAP12 is downregulated in cancer tissues through promoter hypermethylation, and may have a role as a candidate tumor suppressor gene for HCC. J. Surg. Oncol. 2012;105: 381-386. (C) 2011 Wiley Periodicals, Inc.

关键词： expression array single nucleotide polymorphism array hypermethylation

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The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2011年第37期108卷 15201-15206页

作者： Wang, Beatrice T. Ducker, Gregory S. Barczak, Andrea J. Barbeau, Rebecca Erle, David J. Shokat, Kevan M. Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94158 USA Univ Calif San Francisco Dept Cellular & Mol Pharmacol San Francisco CA 94158 USA Univ Calif Berkeley Dept Chem Berkeley CA 94720 USA Univ Calif San Francisco Lung Biol Ctr San Francisco CA 94158 USA

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin inhibits only a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. A number of studies have highlighted mTORC1 as a regulator of lipid homeostasis. We show that the ATP-competitive inhibitor PP242, but not rapamycin, significantly down-regulates cholesterol biosynthesis genes in a 4E-BP1-dependent manner in NIH 3T3 cells, whereas S6 kinase 1 is the dominant regulator in hepatocellular carcinoma cells. To identify other rapamycin-resistant transcriptional outputs of mTOR, we compared the expression profiles of NIH 3T3 cells treated with rapamycin versus PP242. PP242 caused 1,666 genes to be differentially expressed whereas rapamycin affected only 88 genes. Our analysis provides a genomewide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.

关键词： sterol regulatory element-binding protein-2 eIF4E-binding protein-1 phosphorylation 3-hydroxy-3-methylglutaryl-CoA reductase thioredoxin interacting protein expression array

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