Translational pathology of neoplasia

Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Cancer biomarkers: section A of Disease markers (Impact Factor: 1.72). 01/2011; 9(1-6):7-20. DOI: 10.3233/CBM-2011-0159
Source: PubMed


With the increasing use of individualized medical care (personalized medicine) in treating and managing patients with cancer, the utilization of biomarkers in selecting and tailoring such medical approaches also is increasing and becoming more important. Specifically, many therapies are effective against only a subgroup of a specific type of tumors and exposing patients with different non-responsive subgroups of the same tumor to ineffective therapies, not only exposes these patients needlessly to acute and chronic side effects of the therapy, but also adds to the costs of medical care. For example, the Oncotype Dx test for estrogen receptor positive tumors that are node negative has been used to identify low risk tumors for which surgery alone is an adequate therapy. Biomarkers may be used to aid in multiple aspects of medical care related to cancer, including early detection, diagnosis, risk assessment, as well as in predicting the aggressiveness of cancers (i.e., prognosis) and predicting the therapeutic efficacy of treatments (i.e., prediction). Biomarkers may be also used as surrogate endpoints to aid in evaluating therapies and preventive approaches. Types of biomarkers vary greatly and include histopathologic appearance, stage of the lesion, quantitative morphologic features, size of the lesion, metastatic pattern and extent of metastasis, as well as imaging and molecular features. The types of measurements of biomarkers also vary; for example, molecular features can be measured at the DNA, mRNA or protein levels as well as at regulatory levels (e.g., microRNA). The usefulness of each biomarker is limited by its sensitivity and specificity in fulfilling its role (e.g., in early detection) and the requirements of sensitivity and specificity to accomplish specific tasks are affected by multiple variables. For example, both very high specificity and sensitivity of a test are required to screen a population with a low prevalence of a specific tumor. The goal of this manuscript is to introduce the reader to how biomarkers may be used and the limitations on the uses of biomarkers in translational research.

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    ABSTRACT: The availability of human tissues to support biomedical research is critical to advance translational research focused on identifying and characterizing approaches to individualized (personalized) medical care. Providing such tissues relies on three acceptable models - a tissue banking model, a prospective collection model and a combination of these two models. An unacceptable model is the "catch as catch can" model in which tissues are collected, processed and stored without goals or a plan or without standard operating procedures, i.e., portions of tissues are collected as available and processed and stored when time permits. In the tissue banking model, aliquots of tissues are collected according to SOPs. Usually specific sizes and types of tissues are collected and processed (e.g., 0.1 gm of breast cancer frozen in OCT). Using the banking model, tissues may be collected that may not be used and/or do not meet specific needs of investigators; however, at the time of an investigator request, tissues are readily available as is clinical information including clinical outcomes. In the model of prospective collection, tissues are collected based upon investigator requests including specific requirements of investigators. For example, the investigator may request that two 0.15 gm matching aliquots of breast cancer be minced while fresh, put in RPMI media with and without fetal calf serum, cooled to 4°C and shipped to the investigator on wet ice. Thus, the tissues collected prospectively meet investigator needs, all collected specimens are utilized and storage of specimens is minimized; however, investigators must wait until specimens are collected, and if needed, for clinical outcome. The operation of any tissue repository requires well trained and dedicated personnel. A quality assurance program is required which provides quality control information on the diagnosis of a specimen that is matched specifically to the specimen provided to an investigator instead of an overall diagnosis of the specimen via a surgical pathology report. This is necessary because a specific specimen may not match the diagnosis of the case due to many factors such as necrosis, unsuspected tumor invasion of apparently normal tissue, and areas of fibrosis which are mistaken grossly for tumor. Aliquots for quality control (QC) may or may not be collected at the time of collection and in some cases, QC may not occur until specimens are distributed to investigators. In establishing a tumor repository, multiple issues need to be considered. These include the available resources, long term support, space and equipment. The needs of the potential users need to be identified as to the types of tissues and services needed and the annotation expected. Other specific issues to be considered include collection of specimens potentially infected with blood borne pathogens (e.g., hepatitis B), charge back mechanisms, informatics needs and support, and investigator requirements (e.g., recognition of repository contributions in publications). In general, the repository should not perform the research of the investigators, but should provide the infrastructure necessary to support the research of the investigator. Thus, the goals of the repository must be established. Similarly, ethical and regulatory issues must be evaluated. In general, tissue repositories need ethical (e.g., IRB) and privacy (e.g., HIPAA) review. Also, safety issues need to be considered as well as how biohazards will be addressed by investigator-users. Considerations involving the transfer of specimens to other organization usually require a material transfer agreement (MTA). A MTA should address biohazards as well as indemnification. Thus, many issues must be considered and addressed in order to establish and operate successfully a biorepository.
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    ABSTRACT: It has become increasingly evident that the study of DNA is inadequate to explain many, if not most, aspects of the development and progression of neoplastic lesions from pre-invasive lesions to metastasis. Thus, the term "genetic" can no longer refer to just the study of the genome. Much of the action in genetic research now shifts to the methods by which the pre-mRNA from one gene is processed to yield multiple different proteins, different quantities of the same protein as well as other forms of regulating RNA. Thus, the age of post-transcriptional processing and epigenetic control of the transfer of information from the genome has arrived. The mechanisms of post-transcriptional processing and epigenetic control that must be characterized in greater detail including alternate splicing, regulation of mRNA degradation, RNA regulatory factors including those factors which extensively edit mRNAs, control of translation, and control of protein stability and degradation. This chapter reviews many of the processes that control information from the genome to proteins and how these factors lead from less than 40,000 genes to more than an order of magnitude increase more proteins which actually control the phenotypes of cells - normal or neoplastic. It is usually the products of genes (e.g., mRNA, microRNA and proteins) that are the molecular markers that will control translational research and ultimately, individualized (personal) medical approaches to disease. This chapter emphasizes how the process of neoplasia "hijacks" the normal processes of cellular operations, especially those processes that are important in the normal development of the organisms - including proliferation, cellular death, angiogenesis, cellular mobility and invasion, and immunoregulation to ensure neoplastic development, survival and progression. This chapter reviews the wide range of processes controlling the information that flows from the genome to proteins and emphasizes how molecular steps in pure processes can be used as biomarkers to study prevention, treatment and/or management of diseases.
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