GLOSSARY

Allele—any one of a series of two or more different genes that occupy the same position (locus) on a chromosome.

Amplification—a process by which specific genetic material is increased. For some cancers, the number of copies of specific genes is higher than normal. These genes are said to be amplified.

Analyte-specific reagent (ASR)—antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents, which through specific binding or chemical reaction with substances in a specimen are intended to be used in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.

Analytical validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis.

Base substitution—the replacement in a genetic sequence of one nitrogenous base for another. There are four bases for the nucleotides that comprise DNA. These bases are adenine, cytosine, guanine, and thymine. Base substitutions can cause cancer. Base substitutions are also called point mutations.

BRCA—a gene that when mutated increases a woman’s risk of developing breast cancer. Two BRCA genes have been identified and are known as BRCA1 and BRCA2.

Clinical endpoint—a characteristic or variable that reflects how a patient feels, functions, or survives.

Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effectiveness of procedures or interventions in humans.

Clinical utility—the clinical and psychological benefits and risks of positive and negative results of a given technique or test.

Clinical validity—the accuracy of a test for a specific clinical purpose, such as diagnosing or predicting risk for a disorder.

Comparative genomic hybridization—a technique for detecting the gain or loss of genetic material in tumor cells. This technique involves using different-colored fluorescent labels to compare tumor genetic material to that of normal cells. The tumor DNA sequences bind with corresponding sequences in normal cells such that any extra or missing genetic material is readily detected.



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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics GLOSSARY Allele—any one of a series of two or more different genes that occupy the same position (locus) on a chromosome. Amplification—a process by which specific genetic material is increased. For some cancers, the number of copies of specific genes is higher than normal. These genes are said to be amplified. Analyte-specific reagent (ASR)—antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents, which through specific binding or chemical reaction with substances in a specimen are intended to be used in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens. Analytical validity—the accuracy of a test in detecting the specific entity that it was designed to detect. This accuracy does not imply any clinical significance, such as diagnosis. Base substitution—the replacement in a genetic sequence of one nitrogenous base for another. There are four bases for the nucleotides that comprise DNA. These bases are adenine, cytosine, guanine, and thymine. Base substitutions can cause cancer. Base substitutions are also called point mutations. BRCA—a gene that when mutated increases a woman’s risk of developing breast cancer. Two BRCA genes have been identified and are known as BRCA1 and BRCA2. Clinical endpoint—a characteristic or variable that reflects how a patient feels, functions, or survives. Clinical trial—a formal study carried out according to a prospectively defined protocol that is intended to discover or verify the safety and effectiveness of procedures or interventions in humans. Clinical utility—the clinical and psychological benefits and risks of positive and negative results of a given technique or test. Clinical validity—the accuracy of a test for a specific clinical purpose, such as diagnosing or predicting risk for a disorder. Comparative genomic hybridization—a technique for detecting the gain or loss of genetic material in tumor cells. This technique involves using different-colored fluorescent labels to compare tumor genetic material to that of normal cells. The tumor DNA sequences bind with corresponding sequences in normal cells such that any extra or missing genetic material is readily detected.

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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics Computed tomography—a special radiographic technique that uses a computer to assimilate multiple x-ray images into a two-dimensional, cross-sectional image, which also can be reconstructed into a three-dimensional image. This can reveal many soft-tissue structures not shown by conventional radiography. De novo classification—a Food and Drug Administration (FDA) classification of a device or diagnostic that is not equivalent to a legally marketed product. Deletion—the loss of genetic material. Some cancers are triggered by the deletion of key genes, portions of genes, or their regulatory sequences. Epidermal growth factor receptor (EGFR)—a receptor that is overproduced in several solid tumors, including breast and lung cancers. Its overproduction is linked to a poorer prognosis because it enables cell proliferation, migration, and the development of blood vessels. Several new drugs recently approved by the FDA specifically target EGFR. Flow cytometry—a technique for identifying and sorting cells and their components (such as DNA) by staining with fluorescent dyes and detecting the fluorescence, usually by laser beam illumination. Genome—an organism’s entire complement of DNA, which determines its genetic makeup. Genomics—the study of all of the nucleotide sequences, including structural genes, regulatory sequences, and noncoding DNA segments, in the chromosomes of an organism or tissue sample. The application of genomics in oncology involves using microarray or other techniques to uncover the genetic “fingerprint” of a tissue sample. This genetic fingerprint is the pattern that stems from the various amounts and types of all the genetic sequences in the sample. Genotype—the genetic makeup of an organism or cell. High-density expression arrays—microarrays with so many probes that they can detect the expression of hundreds of thousands of genes, as opposed to low-density expression arrays, which can detect a much smaller number. High-throughput technology—any approach using robotics, automated machines, and computers to process many samples at once. Home-brew test—diagnostic tests that are custom made in individual laboratories by combining several reagents in a specified protocol. All testing of a home-brew diagnostic is done within the laboratory that developed it. The FDA regulates commercial tests through premarket

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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics approval (PMA) or premarket notification (510[k]) review process. In contrast, the FDA does not regulate home-brew tests, except to the extent that they use ASRs. Clearance or approval of the test itself is not required. Liquid chromatography—a process in which a chemical mixture carried by a liquid or gas is separated into its components due to the different rates at which these components travel through a stationary liquid. Loss of heterozygosity (LOH)—loss of one allele at a specific position on a chromosome. Magnetic resonance imaging—method by which images are created by recording signals generated from the excitation (the gain and loss of energy) of elements such as the hydrogen of water in tissue when placed within a powerful magnetic field and pulsed with radio frequencies. Mass spectroscopy—a method for separating ionized molecular particles according to mass by applying a combination of electrical and magnetic fields to deflect ions passing in a beam through the instrument. Messenger RNA (mRNA) expression profiling—the use of microarrays or other technology to quantify all the different mRNAs transcribed from the various protein-encoding genes in a sample. (Messenger RNA carries the information from the DNA genetic code to areas in the cytoplasm of the cell in which proteins are made.) Metabolomics—the systematic study of the unique chemical fingerprints that specific cellular processes leave behind, i.e., small-molecule metabolites. Microarray—a high-throughput biological assay in which different probes are deposited on a chip surface (glass or silicon) in a miniature arrangement. DNA microarrays are the most commonly used microarrays. Pharmacodynamics—the study of the biochemical and physiological effects of drugs, the mechanisms of drug action, and the relationship between drug concentration and effect. Pharmacodynamics is the study of what a drug does to the body, as opposed to pharmacokinetics, which is the study of what a body does to a drug. Pharmacogenomics—a biotechnological science that combines the techniques of medicine, pharmacology, and genomics and is concerned with developing drug therapies to compensate for genetic differences in patients that cause varied responses to a single therapeutic regimen. Pharmacokinetics—the study of the time course of substances, such as drugs, in an organism. Pharmacokinetics is used to determine how quickly and for how long a drug acts on its target.

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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics Phase I trial—clinical trial in a small number of patients in which the toxicity and dosing of an intervention are assessed. Phase II trial—clinical trial in which the safety and preliminary efficacy of an intervention are assessed in patients. Phase III trial—large-scale clinical trial in which the safety and efficacy of an intervention are assessed in a large number of patients. The FDA generally requires new drugs to be tested in Phase III trials before they can be put on the market. Phenotype—the physical traits of an individual. Phosphorylated proteins—proteins to which a phosphate group has been attached. The excessive growth that typifies cancer is often thought to be prompted by the phosphorylation of growth-signaling proteins called tyrosine kinases. Such phosphorylation activates these molecules. Polyacrylamide gel electrophoresis (two-dimensional)—a technique used to separate molecules out of a solution based on their charge, isoelectric point, mass, and size. One-dimensional electrophoresis, in contrast, has fewer molecule-distinguishing capabilities, as it only separates molecules out of a solution based on their charge and size. Polymerase chain reaction (PCR)—a technique for duplicating genetic sequences in vitro by as many as a billion times. This technique enables the detection of relatively scarce genetic material. Polymorphism—existence of a gene in several allelic forms. Positron emission tomography—a highly sensitive technique that uses radioactive probes to image in vivo tumors, receptors, enzymes, DNA replication, gene expression, antibodies, hormones, drugs and other compounds or processes. Predictive value—the likelihood that a positive test result indicates a specific diagnosis or that a negative test result excludes that diagnosis. Premarket approval (PMA)—an FDA approval for a new test or device that enables it to be marketed for clinical use. To receive this approval, the manufacturer of the product must submit clinical data showing the product is safe and effective for its intended use. Premarket notification or 510(k)—an FDA review process that enables a new test or device to be marketed for clinical use. This review process requires manufacturers to submit data showing the accuracy and precision of their product, and in some cases, analytical sensitivity and specificity. Manufacturers also have to provide documentation supporting their claim that their product is substantially equivalent to

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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics one already on the market. This review does not typically consider the clinical safety and effectiveness of the product. Protein chip—a piece of glass or other surface on which different protein probes have been affixed at separate locations in an ordered manner. The probes are often antibodies to specific proteins. The protein chip identifies the amounts and types of proteins present in a sample via fluorescence-based imaging. Proteomics—the study of the structure, function, and interactions of the proteins produced by the genes of a particular cell, tissue, or organism. The application of proteomics in oncology may involve mass spectroscopy, two-dimensional polyacrylamide gel electrophoresis, protein chips, and other techniques to uncover the protein “fingerprint” of a tissue sample. This protein fingerprint is the pattern that stems from the various amounts and types of all the proteins in the sample. Qualification—the evidentiary process of linking an assay with biological and clinical endpoints that is dependent on the intended application. Quality-adjusted life-year index—an index that combines measures of quality of life with length of life. Sanger sequencing—a process used to sequence (read the bases of) DNA. With this technique, the DNA segment to be sequenced is replicated numerous times and compounds are added to randomly stop the creation of DNA at each of the four bases (depending on the substance). This produces pieces of DNA of almost every length, which are then separated via gel electrophoresis. Markers on each strand show with which base the strand ends. When the results from the strands are combined, it is possible to decipher the sequence of bases at any point. Sensitivity (analytical)—the lowest concentration that can be distinguished from background noise. This concentration is termed the assay’s detection limit. Sensitivity (clinical)—a measure of how often a test correctly identifies patients with a specific diagnosis. It is calculated as the number of true-positive results divided by the number of true-positive results and false-negative results. Single-molecule sequencing—also called nanopore sequencing, is a method for sequencing DNA that involves passing the DNA through small pores about 1 nanometer in diameter. The size of the pore ensures that the DNA is forced through the hole as a long string, one base at a time. The base (i.e., adenine, guanine, cytosine, or thymine) is identified by the characteristic obstruction it creates in the pore, which is

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Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics detected electrically. Single-molecule sequencing can be a more sensitive technique for identifying relatively rare genetic strands in a sample, without the need for replicating them with PCR. Single nucleotide polymorphism (SNP)—a variant DNA sequence in which the purine or pyrimidine base (e.g., cytosine) of a single nucleotide has been replaced by another such base (e.g., thymine). SNP microarray—a type of microarray used to identify genetic changes linked to specific cancers, specifically LOH, amplifications, and deletions of regions of DNA. Specificity (analytical)—how well an assay detects only a specific substance and does not detect closely related substances. Specificity (clinical)—a measurement of how often a test correctly identifies the proportion of persons without a specific diagnosis. It is calculated as the number of true-negative results divided by the number of true negatives plus the false positives. Surface-enhanced laser desorption/ionization (SELDI)—a technique that uses chemical or antibody probes to bind to specific proteins in a sample. The bound proteins are then vaporized with a laser and ionized for analysis in a mass spectrometer. Patterns of the masses of the various proteins in a sample, rather than actual protein identifications, are produced by SELDI analysis. These mass spectral patterns are used to differentiate patient samples from one another, such as to distinguish diseased from normal samples. Surrogate endpoint—a biomarker that is intended to substitute for a clinical endpoint in a therapeutic clinical trial and is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Validation—the process of assessing the assay or measurement performance characteristics.