MEDLINE Abstracts: Cancer Genomics
MEDLINE Abstracts: Cancer Genomics
Herrmann JL, Rastelli L, Burgess CE, et al.
Cancer J 2001;7:40-51
The explosion of information generated by large-scale functional genomics technologies has resulted in an exponential increase in the number of potential genes and proteins available for pharmaceutical and diagnostic research development. In order to tap this potential, the primary challenge is to develop a strategy to effectively integrate and extract meaning from the human genomic sequence information that has been generated since the start of the Human Genome Project. This article deals with the strategies being applied by academics and by the biotechnology sector to sort and triage this information with the ultimate goal of identifying future therapeutic targets for cancer and other diseases.
Schultze JL, Vonderheide RH.
Trends Immunol 2001;22:516-523
Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptide-specific T cells can be qualitatively and quantitatively analyzed at the single-cell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy.
Bubendorf L.
Eur Urol 2001;40:231-238
Background: Despite continuous research efforts in the past decades, there are still cancers where no effective treatment is available, such as advanced kidney cancer or hormone-refractory prostate cancer. A better understanding of the molecular mechanisms of cancer development and progression is the basis for the development of new diagnostic and therapeutic strategies. Current developments in genomics have a dramatic impact on the whole field of research. The sequence of the entire human genome will soon be fully sequenced and provide the 'book of life' as a basis for the understanding of human disease.
Methods and Results: New technologies have emerged to translate the human genome sequence into gene function and improved diagnostics or treatment modalities. New technologies such as microarrays are not only important for fundamental research, but will also be useful for diagnostic, prognostic or therapeutic purposes in individual patients. DNA microarrays make it possible to analyze the mRNA expression of thousands of genes simultaneously. The resulting comprehensive gene expression surveys lead to the identification of new genes and pathways with importance in cancer development and progression, or as targets for new therapies. The validation and prioritization of genes emerging from genome screening analyses in large series of clinical tumors has become a new bottleneck in research. Therefore, we have recently developed the tissue microarray (TMA) technology to efficiently test the clinical relevance of candidate genes. TMAs are microscope slides containing samples from hundreds of individual tumor specimens. They can be used for large-scale, massively parallel in situ analysis of genetic alterations on a DNA, RNA and protein level using in situ hybridization or immunohistochemistry on hundreds of tumor specimens at a time. Microarray technologies are already increasingly being used in urologic research, and will also have a strong impact on clinical urology.
Conclusions: DNA microarrays and TMAs provide a powerful approach to identify large numbers of new candidate genes, and rapidly validate their clinical impact in large series of human tumors. These technologies will soon lead to a better molecular understanding of urologic tumors, and accelerate the identification of new prognostic markers or therapeutic targets.
Zhang W, Laborde PM, Coombes KR, Berry DA, Hamilton SR.
Clin Cancer Res 2001;7:2159-2167
The impending final deciphering of the complete human genome, coupled with the advancement of high-throughput technologies, is positioned to bring about a fundamental transformation in cancer research. The era of molecular biology is transforming into the era of genomic biology, with an unprecedented promise of understanding multifactorial diseases and of identifying specific targets that can be used to develop patient-tailored therapies. Although the genomic approach is in an early phase of its development and its tools need to be honed, the application of genomic technologies to cancer research has already generated exciting results both in target identification and in disease classification. In this article, we review some of the developments pertinent to cancer research, discuss potentially problematic areas associated with them, and comment on future trends and issues.
Paik S.
Semin Oncol 2001;28:305-309
The effectiveness of current chemotherapeutic approaches for the treatment of solid tumors has reached a near plateau, suggesting we are nearing the limit of cytoreduction. It is hypothesized that this may be due to "subset effect," and that drugs administered according to responses predicted for particular subgroups within the population being treated could overcome what appears to be a limit of cytoreduction. However, the clinical trial process, as currently structured, prevents efficient discovery and validation of predictive markers of treatment response. An alternative process is proposed, based on preoperative therapy and high-throughput multiplexing of markers to provide a built-in, unbiased discovery and validation process for predictive markers.
Kallioniemi OP.
Ann Med 2001;33:142-147
Development of high-throughput 'biochip' technologies has dramatically enhanced our ability to study biology and explore the molecular basis of disease. Biochips enable massively parallel molecular analyses to be carried out in a miniaturized format with a very high throughput. This review will highlight applications of the various biochip technologies in cancer research, including analysis of 1) disease predisposition by using single-nucleotide polymorphism (SNP) microarrays, 2) global gene expression patterns by cDNA microarrays, 3) concentrations, functional activities or interactions of proteins with proteomic biochips, and 4) cell types or tissues as well as clinical endpoints associated with molecular targets by using tissue microarrays. One can predict that individual cancer risks can, in the future, be estimated accurately by a microarray profile of multiple SNPs in critical genes. Diagnostics of cancer will be facilitated by biochip readout of activity levels of thousands of genes and proteins. Biochip diagnostics coupled with informatics solutions will form the basis of individualized treatment decisions for cancer patients.
Schaefer C, Grouse L, Buetow K, Strausberg RL.
Cancer J 2001;7:52-60
The National Cancer Institute's Cancer Genome Anatomy Project (CGAP) is developing publicly accessible information, technology, and material resources that provide a platform for the interface of cancer research and genomics. CGAP's efforts have focused toward (1) building and annotating catalogues of genes expressed during cancer development, (2) identifying polymorphisms in those genes, and (3) developing resources for the molecular characterization of cancer-related chromosomal aberrations. To date, CGAP has produced more than 1,000,000 expressed sequence tags, approximately 3,300,000 serial analysis of gene expression tags, and identified more than 10,000 human gene-based single-nucleotide polymorphisms. To enhance access to these datasets by the research community, a new Cancer Genome Project Web site (http://cgap.nci.nih.gov/) is being introduced. The web site includes genomic data for humans and mice, including transcript sequence, gene expression patterns, single-nucleotide polymorphisms, clone resources, and cytogenetic information. Descriptions of the methods and reagents used in deriving the CGAP datasets are also provided. An extensive suite of informatics tools facilitates queries and analysis of the CGAP data by the community. One of the newest features of the CGAP web site is an electronic version of the Mitelman Database of Chromosome Aberrations in Cancer.
Herrmann JL, Rastelli L, Burgess CE, et al.
Cancer J 2001;7:40-51
The explosion of information generated by large-scale functional genomics technologies has resulted in an exponential increase in the number of potential genes and proteins available for pharmaceutical and diagnostic research development. In order to tap this potential, the primary challenge is to develop a strategy to effectively integrate and extract meaning from the human genomic sequence information that has been generated since the start of the Human Genome Project. This article deals with the strategies being applied by academics and by the biotechnology sector to sort and triage this information with the ultimate goal of identifying future therapeutic targets for cancer and other diseases.
Schultze JL, Vonderheide RH.
Trends Immunol 2001;22:516-523
Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptide-specific T cells can be qualitatively and quantitatively analyzed at the single-cell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy.
Bubendorf L.
Eur Urol 2001;40:231-238
Background: Despite continuous research efforts in the past decades, there are still cancers where no effective treatment is available, such as advanced kidney cancer or hormone-refractory prostate cancer. A better understanding of the molecular mechanisms of cancer development and progression is the basis for the development of new diagnostic and therapeutic strategies. Current developments in genomics have a dramatic impact on the whole field of research. The sequence of the entire human genome will soon be fully sequenced and provide the 'book of life' as a basis for the understanding of human disease.
Methods and Results: New technologies have emerged to translate the human genome sequence into gene function and improved diagnostics or treatment modalities. New technologies such as microarrays are not only important for fundamental research, but will also be useful for diagnostic, prognostic or therapeutic purposes in individual patients. DNA microarrays make it possible to analyze the mRNA expression of thousands of genes simultaneously. The resulting comprehensive gene expression surveys lead to the identification of new genes and pathways with importance in cancer development and progression, or as targets for new therapies. The validation and prioritization of genes emerging from genome screening analyses in large series of clinical tumors has become a new bottleneck in research. Therefore, we have recently developed the tissue microarray (TMA) technology to efficiently test the clinical relevance of candidate genes. TMAs are microscope slides containing samples from hundreds of individual tumor specimens. They can be used for large-scale, massively parallel in situ analysis of genetic alterations on a DNA, RNA and protein level using in situ hybridization or immunohistochemistry on hundreds of tumor specimens at a time. Microarray technologies are already increasingly being used in urologic research, and will also have a strong impact on clinical urology.
Conclusions: DNA microarrays and TMAs provide a powerful approach to identify large numbers of new candidate genes, and rapidly validate their clinical impact in large series of human tumors. These technologies will soon lead to a better molecular understanding of urologic tumors, and accelerate the identification of new prognostic markers or therapeutic targets.
Zhang W, Laborde PM, Coombes KR, Berry DA, Hamilton SR.
Clin Cancer Res 2001;7:2159-2167
The impending final deciphering of the complete human genome, coupled with the advancement of high-throughput technologies, is positioned to bring about a fundamental transformation in cancer research. The era of molecular biology is transforming into the era of genomic biology, with an unprecedented promise of understanding multifactorial diseases and of identifying specific targets that can be used to develop patient-tailored therapies. Although the genomic approach is in an early phase of its development and its tools need to be honed, the application of genomic technologies to cancer research has already generated exciting results both in target identification and in disease classification. In this article, we review some of the developments pertinent to cancer research, discuss potentially problematic areas associated with them, and comment on future trends and issues.
Paik S.
Semin Oncol 2001;28:305-309
The effectiveness of current chemotherapeutic approaches for the treatment of solid tumors has reached a near plateau, suggesting we are nearing the limit of cytoreduction. It is hypothesized that this may be due to "subset effect," and that drugs administered according to responses predicted for particular subgroups within the population being treated could overcome what appears to be a limit of cytoreduction. However, the clinical trial process, as currently structured, prevents efficient discovery and validation of predictive markers of treatment response. An alternative process is proposed, based on preoperative therapy and high-throughput multiplexing of markers to provide a built-in, unbiased discovery and validation process for predictive markers.
Kallioniemi OP.
Ann Med 2001;33:142-147
Development of high-throughput 'biochip' technologies has dramatically enhanced our ability to study biology and explore the molecular basis of disease. Biochips enable massively parallel molecular analyses to be carried out in a miniaturized format with a very high throughput. This review will highlight applications of the various biochip technologies in cancer research, including analysis of 1) disease predisposition by using single-nucleotide polymorphism (SNP) microarrays, 2) global gene expression patterns by cDNA microarrays, 3) concentrations, functional activities or interactions of proteins with proteomic biochips, and 4) cell types or tissues as well as clinical endpoints associated with molecular targets by using tissue microarrays. One can predict that individual cancer risks can, in the future, be estimated accurately by a microarray profile of multiple SNPs in critical genes. Diagnostics of cancer will be facilitated by biochip readout of activity levels of thousands of genes and proteins. Biochip diagnostics coupled with informatics solutions will form the basis of individualized treatment decisions for cancer patients.
Schaefer C, Grouse L, Buetow K, Strausberg RL.
Cancer J 2001;7:52-60
The National Cancer Institute's Cancer Genome Anatomy Project (CGAP) is developing publicly accessible information, technology, and material resources that provide a platform for the interface of cancer research and genomics. CGAP's efforts have focused toward (1) building and annotating catalogues of genes expressed during cancer development, (2) identifying polymorphisms in those genes, and (3) developing resources for the molecular characterization of cancer-related chromosomal aberrations. To date, CGAP has produced more than 1,000,000 expressed sequence tags, approximately 3,300,000 serial analysis of gene expression tags, and identified more than 10,000 human gene-based single-nucleotide polymorphisms. To enhance access to these datasets by the research community, a new Cancer Genome Project Web site (http://cgap.nci.nih.gov/) is being introduced. The web site includes genomic data for humans and mice, including transcript sequence, gene expression patterns, single-nucleotide polymorphisms, clone resources, and cytogenetic information. Descriptions of the methods and reagents used in deriving the CGAP datasets are also provided. An extensive suite of informatics tools facilitates queries and analysis of the CGAP data by the community. One of the newest features of the CGAP web site is an electronic version of the Mitelman Database of Chromosome Aberrations in Cancer.
Source...