[Cancer: three eras of personalized medicine]. / Cancer : les trois époques de la médecine personnalisée - Chroniques génomiques.

Since the completion of the first human DNA sequence, genomic approaches have penetrated into cancer research and therapy: first through expression profiling for diagnostic, prognostic and predictive purposes, then by sequencing of tumour DNA in order to define and apply targeted therapies. These overlapping changes occurred quite rapidly and are now overshadowed by immuno-oncology approaches that show much promise. There is however still much left to understand to make this more widely applicable, and the extreme cost of these therapies is a serious concern.

Population Screening for Hemoglobinopathy Profiling: Is the Development of a Microarray Worthwhile?

In order to perform affordable and expedient whole population scans for the single nucleotide polymorphisms (SNPs) involved in hemoglobinopathies, microarrays based on single nucleotide extension (SNE) might prove advantageous to whole genome/exome sequencing in terms of cost, speed, interpretation and discretion as they focus on a very small part of the tested genome. The development of a microarray assay entails most of the cost, to be deferred by the massive use of the end product. A microarray assay development project, involving multiplex polymerase chain reaction (PCR), labeling, hybridization and scanning/scoring steps is presented as a paradigm of objective bug ratios expected to such procedures and of ways to cope with them. Qualification of the microarray genotypes needs a reference method, which may still be restriction digestion or other, as sequencing remains an expensive commodity. Optimization of wet steps should also be followed by careful and perhaps individualized dye excitation and in silico scoring rules, taking into consideration decay and bleaching effects that perplex development. The strategy of successive elimination of problems, a top-bottom procedure, which had been used and is usually preferred by developing agencies, might have been erroneous; a bottom-up course to delineate issues in different levels, although more laborious, might be the correct choice, especially as software and robotic hardware, high throughput tools become more mature and available. The testing for interlocus compatibility, specificity and robustness is demanding and warranted only in the case of steady, high volume use of an assay for territorial, national or international use.

[The emergence and development of gene expression profiling: a key component of the 3B (bench, bedside, bytes) in translational research]. / Les réseaux de l'expression génique - Émergence et développement d'un domaine clé de la génomique.

This paper examines the emergence and development of one of the key components of genomics, namely gene expression profiling. It does so by resorting to computer-based methods to analyze and visualize networks of scientific publications. Our results show the central role played by oncology in this domain, insofar as the initial proof-of-principle articles based on a plant model organism have quickly led to the demonstration of the value of these techniques in blood cancers and to applications in the field of solid tumors, and in particular breast cancer. The article also outlines the essential role played by novel bioinformatics and biostatistical tools in the development of the domain. These computational disciplines thus qualify as one of the three corners (in addition to the laboratory and the clinic) of the translational research triangle.

Nutrigenomics: implications for breast and colon cancer prevention.

Nutrigenomics refers to the interaction between one's diet and his/her genes. These interactions can markedly influence digestion, absorption, and the elimination of bioactive food components, as well as influence their site of actions/molecular targets. Nutrigenomics comprises nutrigenetics, epigenetics, and transcriptomics, coupled with other "omic," such as proteomics and metabolomics, that apparently account for the wide variability in cancer risk among individuals with similar dietary habits. Multiple food components including essential nutrients, phytochemical, zoochemicals, fungochemical, and bacterochemicals have been implicated in cancer risk and tumor behavior, admittedly with mixed results. Such findings suggest that not all individuals respond identically to a diet. This chapter highlights the influence of single-nucleotide polymorphism, copy number, epigenetic events, and transcriptomic homeostasis as factors influencing the response to food components and ultimately health, including cancer risk. Both breast and colorectal cancers are reviewed as examples about how nutrigenomics may influence the response to dietary intakes. As the concept that "one size fits all" comes to an end and personalized approaches surface, additional research data will be required to identify those who will benefit most from dietary change and any who might be placed at risk because of an adjustment.

Is gene array testing to be considered routine now?

BACKGROUND: There are five multi-gene expression based prognostic tests for breast cancer offered as reference lab tests - Mammaprint, MapQuant Dx, OncotypeDx, PAM50 Breast Cancer Intrinsic Subtype Classifier, and Theros Breast Cancer Index. Each claims to provide additional prognostic information beyond conventional prognostic markers and to aid in determining who should receive systemic therapy. Evidence for their clinical utility was reviewed to determine whether any of them should be considered as routine clinical test. METHODS: Peer reviewed publications, meeting abstracts, and information provided by company web sites have been reviewed to compile information regarding their clinical utility according to the following criteria; (1) Analytical validity and regulatory approval of the reference lab test. (2) Level of evidence for clinical utility. (3) Whether published evidences support prognostic and/or predictive claim. RESULTS: While published evidences for clinical claims for OncotypeDx and Mammaprint used reference lab tests, and the supporting evidences for other tests come from academic assays before being converted to reference lab tests, results from two large randomized clinical trials testing the clinical utility of OncotypeDx and Mammaprint are still several years away and until that time none of the markers would reach level I evidence by Marker Utility Grading System. However Oncotype Dx has reached a level IB evidence according to Simon modification to Marker Utility Grading System. Therefore OncotypeDx may be considered for routine clinical use as an adjunct to clinical and pathological information and has been incorporated into clinical guidelines in USA. While Mammaprint, MapQuantDx, and PAM50 have been repeatedly demonstrated to provide robust prognostic information, evidence for its worth as a predictive marker for chemotherapy benefit is yet to come from randomize clinical trials and therefore its utility is limited to prognostication. Meta-analysis of publicly available microarray based gene expression studies demonstrated that gene expression assays provide similar information and the most important information they provide is the proliferation activity. In untreated population, the prognostic impact of proliferation genes is limited to ER+HER2- subset since HER2+ or ER-HER2- subsets are associated with high proliferation activity. Therefore the clinical utility of these gene expression based tests is mainly for ER+HER2- subset. Since they are usually treated with adjuvant anti-estrogen therapies, for their clinical utility, demonstration of the interaction between the gene expression markers and chemotherapy in anti-estrogen treated cohort in a randomized clinical trial would be required. While OncoytpeDx is the only test supported by studies in a randomized clinical trial for adjuvant chemotherapy, other gene expression based tests are expected to provide similar information. Gene expression profiling assays as more reproducible and precise surrogates for tumor grade (MapQauntDx and Theros Breast Cancer Index) are very promising assays. However, absence of definitive predefined cut-off for defining the subset that benefit from chemotherapy validated in cohorts from randomized trials limit their clinical application.

Therapeutic and diagnostic applications of nanoparticles.

Nanoparticles are sphere-like biocompatible materials made of inert silica, metal or crystals of a few nanometers in size. They are emerging as a novel class of therapeutics for cancer treatment. Being more selective and specific toward their targets, nanoparticles have the ability to enhance the anticancer effects and to simultaneously reduce systemic toxicity compared with conventional therapeutics. Furthermore, they offer the potential to overcome drug resistance leading to higher intracellular drug accumulation. Nowadays, nanotechnologies are applied to molecular diagnostics and incorporated in cutting-edge molecular diagnostic methods, such as DNA and protein microarray biochips. Nanotechnologies enable diagnosis at the single-cell and single-molecule levels. Recent progress in cancer nanotechnology raises exciting opportunities for specific drug delivery. The purpose of this review is to give an overview about different types of nanoparticles and to summarize the latest results regarding their diagnostic and therapeutic applications in the clinic with more focus on cancer treatment. Furthermore, we discuss opportunities, limitations, and challenges faced by therapeutic nanoparticles.

New development of glycan arrays.

The development of glycan arrays has enabled the high-sensitivity and high-throughput analysis of carbohydrate-protein interactions and contributed to significant advances in glycomics. A number of new array platforms that allow for qualitative and quantitative analysis of mono- and multivalent interactions on surfaces have been developed recently. Glycan arrays are not only a powerful tool for basic research, but also a promising technique for medical diagnosis, and detection of pathogens and cancers. These studies also have led to the design of efficient carbohydrate-based antimicrobial or anticancer vaccines.

Highlights of the annual meeting of the Italian Association for Cell Cultures (AICC): new drug delivery strategies and technological platforms for diagnosis and therapy of tumors (Part I) 6 - 7 December 2007, Naples, Italy.

The application of computational analysis to biochemistry and molecular biology techniques has allowed the design of advanced technological platforms such as DNA microarrays, proteomic analysis and tissue microarrays. These are useful in the diagnosis of tumors and in driving the choice of opportune therapeutic options. The use of target-based agents requires the determination of the molecular features of the tumors. During the AICC meeting four new advanced technological platforms were analyzed: DNA microarrays, ProtoArrays, tissue microarrays and proteomic analysis with differential in-gel electrophoresis (DIGE) and matrix-associated laser desorption ionization-time of flight (MALDI-TOF). The use of DNA microarray in the study of neo-angiogenic components in tumor tissues was described and the ex vivo analysis in humans of circulating endothelial cells was proposed. The role of both genomic and pharmacogenomic profiles in the diagnosis and prediction of response to therapy and toxicity of both breast and colorectal cancer was described. A developmental model for the optimization of zoledronic acid (ZOL) antitumor activity based on either nanotechnological modification or molecular target fishing with DNA microarrays was discussed. The interdisciplinary network between pharmacologists, cellular and molecular biologists, biochemists and translational and clinical oncologists was encouraged and approved during the meeting in order to improve the efficacy of antitumor strategies.

Moving cancer diagnostics from bench to bedside.

To improve treatment and reduce the mortality from cancer, a key task is to detect the disease as early as possible. To achieve this, many new technologies have been developed for biomarker discovery and validation. This review provides an overview of omics technologies in biomarker discovery and cancer detection, and highlights recent applications and future trends in cancer diagnostics. Although the present omic methods are not ready for immediate clinical use as diagnostic tools, it can be envisaged that simple, fast, robust, portable and cost-effective clinical diagnosis systems could be available in near future, for home and bedside use.

A pipeline for ligand discovery using small-molecule microarrays.

Uncovering the functions of thousands of gene products, in various states of post-translational modification, is a key challenge in the post-genome era. To identify small-molecule probes for each protein function, high-throughput methods for ligand discovery are needed. In recent years, small-molecule microarrays (SMMs) have emerged as high-throughput and miniaturized screening tools for discovering protein-small-molecule interactions. Microarrays of small molecules from a variety of sources, including FDA-approved drugs, natural products and products of combinatorial chemistry and diversity-oriented synthesis, have been prepared and screened by several laboratories, leading to several newly discovered protein-ligand pairs.

From medical images to multiple-biomarker microarrays.

A favorite cliché, often attributed to Yogi Berra, is "Prediction is difficult, especially about the future!" In this brief review, we shall recall some historical difficulties in predicting the future of diagnostic medical imaging--in particular, the modern technologies of CT and MRI--and examine the analogous situation in the emerging technology of diagnostic microarrays for the multiple-biomarker problem. All of these technologies began their lives as ill-conditioned problems, i.e., there was insufficient data to solve the central problem at hand.

From functional genomics to functional immunomics: new challenges, old problems, big rewards.

The development of DNA microarray technology a decade ago led to the establishment of functional genomics as one of the most active and successful scientific disciplines today. With the ongoing development of immunomic microarray technology-a spatially addressable, large-scale technology for measurement of specific immunological response-the new challenge of functional immunomics is emerging, which bears similarities to but is also significantly different from functional genomics. Immunonic data has been successfully used to identify biological markers involved in autoimmune diseases, allergies, viral infections such as human immunodeficiency virus (HIV), influenza, diabetes, and responses to cancer vaccines. This review intends to provide a coherent vision of this nascent scientific field, and speculate on future research directions. We discuss at some length issues such as epitope prediction, immunomic microarray technology and its applications, and computation and statistical challenges related to functional immunomics. Based on the recent discovery of regulation mechanisms in T cell responses, we envision the use of immunomic microarrays as a tool for advances in systems biology of cellular immune responses, by means of immunomic regulatory network models.

Microarray and nanotechnology applications of functional nanoparticles.

Microarrays are a sensitive, specific, miniaturized devices that may be used to detect selected DNA sequences and proteins, or mutated genes associated with human diseases. Several methods have been developed to detect the binding of complementary molecules to microarrays by generating an optical signal. One of the most commonly used molecular labeling methods at present is fluorescence, but its application is expensive due to sophisticated equipment required to design the platform, hybridize it, and interpret the images derived from microarray-based studies. This is a drawback for its use in laboratories and clinical services. Another less expensive procedure having similar sensitivity and specificity is DNA and protein functional nanoparticles (FNP). Nanoparticles are sphere-like biocompatible materials made of inert silica, metal or crystals of a nanometer in size, which are generally coated with a thin gold layer. They may be used as hybridization probes in single nucleotide polymorphism (SNP) screening and to detect biological markers for cancer, infection, and cardiovascular diseases.

Nanoparticles for multiplex diagnostics and imaging.

The drive to understand biology and medicine at the molecular level with accurate quantitation demands much of current high-throughput analysis systems. Nanomaterials and nanotechnology combined with modern instrumentation have the potential to address this emerging challenge. Using a variety of nanomaterials for multiplex diagnostics and imaging applications will offer sensitive, rapid and cost-effective solutions for the modern clinical laboratory. New nanomaterials have been developed with optical-encoding capabilities for selective tagging of a wide range of medically important targets, including bacteria, cancer cells and individual molecules, such as proteins and DNA, in a single assay. We envision further development in this field will provide numerous advanced tools with increased sensitivity and improved multiplexing capability, for unique applications in molecular biology, genomics and drug discovery.

Emerging trends in genetic-based medical diagnostics.

Prior to the publication of the sequencing of the human genome in April 2003, approximately 1,000 genetic tests were available for monogenetic diseases, i.e., those diseases that emanate from a single gene. The Human Genome Project (HGP) offers the data needed to elucidate the more difficult polygenetic diseases and genetic predisposition to diseases, and help explain variability in drug response. Microarray technology utilizing HGP data has made it possible to survey a person's genome. The applications of this technology include minimizing drug reactions and deriving cancer prognoses. This article will address the role of genetic testing in diagnosing and predicting disease now and in the near future.

Microarray analysis of altered gene expression in murine fibroblasts transformed by nickel(II) to nickel(II)-resistant malignant phenotype.

B200 cells are Ni(II)-transformed mouse BALB/c-3T3 fibroblasts displaying a malignant phenotype and increased resistance to Ni(II) toxicity. In an attempt to find genes whose expression has been altered by the transformation, the Atlas Mouse Stress/Toxicology cDNA Expression Array (Clontech Laboratories, Inc., Palo Alto, CA) was used to analyze the levels of gene expression in both parental and Ni(II)-transformed cells. Comparison of the results revealed a significant up- or downregulation of the expression of 62 of the 588 genes present in the array (approximately 10.5%) in B200 cells. These genes were assigned to different functional groups, including transcription factors and oncogenes (9/14; fractions in parentheses denote the number of up-regulated versus the total number of genes assigned to this group), stress and DNA damage response genes (11/12), growth factors and hormone receptors (6/9), metabolism (7/7), cell adhesion (2/7), cell cycle (3/6), apoptosis (3/4), and cell proliferation (2/3). Among those genes, overexpression of beta-catenin and its downstream targets c-myc and cyclin D1, together with upregulated cyclin G, points at the malignant character of B200 cells. While the increased expression of glutathione (GSH) synthetase, glutathione-S-transferase A4 (GSTA4), and glutathione-S-transferase theta (GSTT), together with high level of several genes responding to oxidative stress, suggests the enforcement of antioxidant defenses in Ni-transformed cells.

Moving toward whole-genome analysis: a technology perspective.

PURPOSE: New, highly efficient technologies used in genomic analysis are described, and their implications for health care are discussed. SUMMARY: The availability of the human genome sequence, in confluence with the ability to affordably package it for analysis, is opening new frontiers in biomedical research. On the horizon, personalized medicine--driven by molecular characterization of disease, genetic analysis of the patient, and information technologies designed to enable health care professionals to leverage these tools--promises to fundamentally transform health care. New genetics technologies, such as high-density microarrays, will fuel this research by providing researchers with the ability to comprehensively access the human genome in all its complexity. Some of the most promising areas for application of genetic information are those where society's current needs are greatest: complex, common disorders, such as cancer and cardiovascular disease; drug interactions; inherited genetic disorders that afflict children; and late-onset conditions for which no cure currently exists. The barriers to using genetic information widely in health care are in many cases not technological or economic, but social and political. CONCLUSION: New technology enables efficient, large-scale analysis of the whole genome, genetic variations, and gene expression. Genomic analysis has profound clinical, economic, and social implications for health care.