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      Genetic alteration and gene expression modulation during cancer progression

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          Abstract

          Cancer progresses through a series of histopathological stages. Progression is thought to be driven by the accumulation of genetic alterations and consequently gene expression pattern changes. The identification of genes and pathways involved will not only enhance our understanding of the biology of this process, it will also provide new targets for early diagnosis and facilitate treatment design. Genomic approaches have proven to be effective in detecting chromosomal alterations and identifying genes disrupted in cancer. Gene expression profiling has led to the subclassification of tumors. In this article, we will describe the current technologies used in cancer gene discovery, the model systems used to validate the significance of the genes and pathways, and some of the genes and pathways implicated in the progression of preneoplastic and early stage cancer.

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          Tissue microarrays for high-throughput molecular profiling of tumor specimens.

          Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.
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            Molecular Classification of Cancer: Class Discovery and Class Prediction by Gene Expression Monitoring

            T. Golub (1999)
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              Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses.

              We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.
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                Author and article information

                Journal
                Mol Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                2004
                22 March 2004
                : 3
                : 9
                Affiliations
                [1 ]Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre; 601 West 10th Ave, Vancouver, BC, Canada V5Z 1L3
                Article
                1476-4598-3-9
                10.1186/1476-4598-3-9
                408463
                15035667
                30af23d9-8a21-4695-8dd0-44563b0f4135
                Copyright © 2004 Garnis et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                : 4 February 2004
                : 22 March 2004
                Categories
                Review

                Oncology & Radiotherapy
                proteomics,expression profiles,high throughput technology,cancer progression,tumorigenesis,genomics

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