Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes

<p>Abstract</p> <p>Background</p> <p>Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations.</p> <p>Methods</p> <p>GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes.</p> <p>Results</p> <p>Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg⁺⁺, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-<it>Myc </it>and <it>Trp53 </it>were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in <it>Ras </it>and genes encoding adhesion or cytoskeleton proteins such as integrin, β-catenin, α-catenin, and actin.</p> <p>Conclusion</p> <p>The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.</p

Genomic and molecular classification of breast cancer

At present, the biology of breast cancer remains poorly understood. Currently, lymph node metastases, tumor grade, and size, and expression of hormone receptors provide the only true prognostic and predictive factors related to clinical outcome and response to treatment, respectively. Many other potential candidates have been suggested but, due to their limited predictive power, have not been widely accepted by the general oncological community. These histopathological features do not allow us any insight into breast cancer biology, however, and these prognostic classifications are far from perfect. At present, due to these limitations many clinicians consider prescribing adjuvant treatment to many women with early breast cancer to reduce the risk of relapse, only to benefit a few, thus exposing many patients to unnecessary toxicity. Since the publication of the complete sequence of the human genome however, a new era of research has begun [1]. More than 3 billions base pairs form the 30,000-40,000 genes that code all the required genetic information of a particular individual. The functions of the vast majority of these genes are still unknown. A combination of circumstances, including the advent of array-based technology and progress in the human genome initiative, have provided the ideal opportunity to begin efforts aimed at performing comprehensive molecular and genetic profiling of human cancers. The ability to interrogate tens of thousands of genes simultaneously by using microarray technologies has significantly changed our approach to the analysis of expression profiles, and has also led to an increased understanding of the basic biology of breast cancer. Such comprehensive technologies permit the assessment not only of individual genes, but also of clusters of genes that are coordinately expressed to generate "fingerprints" of biological states of the cells of origin. This is especially important given that it has become increasingly evident that the biology of cancer, particularly solid tumors, is determined by the behavior of many genes, rather than a few. Although there are other techniques that analyze differences in gene expression, none matches the ease and the comprehensive nature of the interrogation associated with c-DNA- or oligonucleotide-based microarray analysis. A list of the terms commonly used in this field is given in Table 30.1. (Table presented). © Springer-Verlag Berlin Heidelberg 2006.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 are responsible for 5%-10% of epithelial ovarian cancers, but the molecular pathways affected by these mutations are unknown. We used complementary DNA (cDNA) microarrays to compare gene expression patterns in ovarian cancers associated with BRCA1 or BRCA2 mutations with gene expression patterns in sporadic epithelial ovarian cancers and to identify patterns common to both hereditary and sporadic tumors. METHODS: Tumor samples from 61 patients with pathologically confirmed epithelial ovarian adenocarcinoma with matched clinicopathologic features were studied, including 18 with BRCA1 founder mutations, 16 with BRCA2 founder mutations, and 27 without either founder mutation (termed sporadic cancers). The cDNA microarrays contained 7651 sequence-verified features. Gene expression data were analyzed with a modified two-sided F test, with P<.0001 considered statistically significant. The expression level of six genes was also studied with reverse transcription-polymerase chain reaction. RESULTS: The greatest contrast in gene expression was observed between tumors with BRCA1 mutations and those with BRCA2 mutations; 110 genes showed statistically significantly different expression levels (P<.0001). This group of genes could segregate sporadic tumors into two subgroups, "BRCA1-like" and "BRCA2-like," suggesting that BRCA1-related and BRCA2-related pathways are also involved in sporadic ovarian cancers. Fifty-three genes were differentially expressed between tumors with BRCA1 mutations and sporadic tumors; six of the 53 mapped to Xp11.23 and were expressed at higher levels in tumors with BRCA1 mutations than in sporadic tumors. Compared with the immortalized ovarian surface epithelial cells used as reference, several interferon-inducible genes were overexpressed in the majority of tumors with a BRCA mutation and in sporadic tumors. CONCLUSIONS: Mutations in BRCA1 and BRCA2 may lead to carcinogenesis through distinct molecular pathways that also appear to be involved in sporadic cancers. Sporadic carcinogenic pathways may result from epigenetic aberrations of BRCA1 and BRCA2 or their downstream effectors.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.info:eu-repo/semantics/publishe

Molecular profiles of invasive mucinous and ductal carcinomas of the breast: a molecular case study.

Expression profiling using cDNA microarrays have redefined the molecular classification of some cancers. The comprehensive genetic analysis also permits the identification of novel pathways that might determine subtle differences in tumor phenotype. Herein, we analyzed the tissues from a patient with bilateral cancer of different histologies in each breast (pure invasive mucinous and pure invasive ductal), thus providing a unique opportunity to assess the expression profiles determined by histology in an isogenic human background. Our results show that the mucinous phenotype is associated with the expression of immunostimulatory and inhibitory genes, consistent with the cellular infiltration of lymphocytes and with the expression of enzymes involved in mucin production. Moreover, the panel of matrix metallo-proteinases are distinctly different between the mucinous and the invasive tumors, suggesting that therapeutic targets to this class of compounds may need to be tailored for the varying histologies. Taken together, these data suggest that expression profiling can be used diagnostically to distinguish individual histologic subclassifications and may guide the selection of target therapeutics.Case ReportsJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.FLWINinfo:eu-repo/semantics/publishe

Molecular determinants of tumor differentiation in papillary serous ovarian carcinoma.

In epithelial ovarian cancer, tumor grade is an independent prognosticator whose molecular determinants remain unknown. We investigated patterns of gene expression in well- and poorly differentiated serous papillary ovarian and peritoneal carcinomas with cDNA microarrays. A 6500-feature cDNA microarray was used for comparison of the molecular profiles of eight grade III and four grade I stage III serous papillary adenocarcinomas. With a modified F-test in conjunction with random permutations, 99 genes whose expression was significantly different between grade I and grade III tumors were identified (P < 0.01). A disproportionate number of these differentially expressed genes were located on the chromosomal regions 20q13 and all exhibited higher expression in grade III tumors. Interphase fluorescent in situ hybridization demonstrated 20q13 amplification in two of the four grade III and none of the three grade I tumors available for evaluation. Several centrosome-related genes also showed higher expression in grade III tumors. We propose a model in which tumor differentiation is inversely correlated with the overexpression of several oncogenes located on 20q13, a common amplicon in ovarian and numerous other cancers. Dysregulation of centrosome function is one potential mechanistic link between genetic/epigenetic changes and the poorly differentiated phenotype in ovarian cancer.Journal Articleinfo:eu-repo/semantics/publishe

Prediction of early distant relapses on tamoxifen in early-stage breast cancer (BC): A potential tool for adjuvant aromatase inhibitor (AI) tailoring

info:eu-repo/semantics/publishe

Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes-2

<p><b>Copyright information:</b></p><p>Taken from "Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes"</p><p>http://www.biomedcentral.com/1471-2407/7/109</p><p>BMC Cancer 2007;7():109-109.</p><p>Published online 26 Jun 2007</p><p>PMCID:PMC1929113.</p><p></p>ere added to the upper left corner of the gene box (green icon, with 4 numbers to represent a particular KEGG gene ID). Each square is associated with a library and highlighted with red, yellow, or blue color to indicate that gene isoforms are all matched, partially matched, or completely unmatched, respectively, by PETs of the library. By placing the cursor on a particular entity (mouse on), one can view the description of all gene isoforms in the gene box (II), or PET counts, in cpm (counts per million), of a corresponding gene isoform for each library (III & IV). In response to a clicking on a solid square, detailed mapping information is displayed (V). Hyperlinks in II lead to all KEGG pathway images that contain the selected gene isoform

Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes-0

<p><b>Copyright information:</b></p><p>Taken from "Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes"</p><p>http://www.biomedcentral.com/1471-2407/7/109</p><p>BMC Cancer 2007;7():109-109.</p><p>Published online 26 Jun 2007</p><p>PMCID:PMC1929113.</p><p></p> each active 'gene box' (green), two solid squares are added to the upper left corner to reflect the associated information for the Melan-a2 melanocyte library (SMN001_36623nr2, left) and the B16F1 melanoma library (SMT001_32267nr2, right). PET counts associated with each gene isoform can be accessed by clicking on the library squares. Gene isoform-associated PET counts of the melanocyte library and the melanoma library are displayed side by side and compared to demonstrate the transcriptional downregulation of these gene isoforms in melanoma cells. PET counts are normalized to cpm (counts per million)