Safety biomarkers

Related Terms

Biological markers, biological tumor markers, bridging biomarkers, cancer, disease onset biomarkers, DNA markers, efficacy biomarkers, exclusion biomarkers, genetic biomarkers, genetic markers, genomic biomarkers, immunohistochemistry, inclusion biomarkers, markers, metabolic biomarkers, metabolite biomarkers, metabolomic biomarkers, monitoring biomarkers, occurrence biomarker, protein biomarkers, proteomic biomarkers, safety biomarkers, staging biomarkers, surrogate markers, target biomarkers, toxicity biomarkers.

Background

Genetic biomarkers provide an estimate of how genetic variations, also called mutations or polymorphisms, make individuals susceptible to environmental agents. They can help predict disease susceptibility, outcome, and treatment response and toxicity. Biomarkers of susceptibility help identify risks and prevent adverse health effects through prevention and intervention strategies. Other measurable properties of a patient may be used as biomarkers. These include messenger RNA expression profiles, proteins, fats (lipids), imaging methods, and electrical signals.
Genetic markers can suggest why some smokers get cancer but others do not, why some people have a higher incidence of cancer after exposure to a toxicant and others do not, and why some women are more prone to breast cancer than others. Scientists estimate that as many as 80% of cancer deaths in the United States could be prevented because most malignancies are caused by external factors instead of inherent biological conditions. Genetic biomarkers fall into three categories: markers of exposure, markers of effect, and markers of susceptibility.
Exposure: Markers of exposure identify a xenobiotic compound (a substance that exists outside living systems) and how it interacts with an organism. Xenobiotic compounds can originate in food, air, water, and soil. External exposure relates to the degree of xenobiotic substance a person is exposed to and the quantity of a compound that is absorbed into the body.
Carcinogenic agents cause mutations, cancer, and birth defects. Numerous studies have identified 40 agents in drinking water, 60 agents among industrial chemicals released into the air, and 66 agents found in pesticides that are known or potential carcinogens. Biomarkers of exposure are measurable properties in an individual that provide early signs of biological change caused by his or her exposure to chemicals and drugs. For example, the gene that provides instructions for making the liver enzyme that helps to break down drugs and environmental agents, cytochrome P450 1A1, is expressed more frequently in individuals with significant exposure to diesel exhaust.
Effect: Biological markers of effect identify disease presence, disease precursors, or events that predict a disease process or impaired health. Biological markers of effect can be used for disease diagnosis or determining its prognosis. Markers of effect can manifest as changes in target tissue function or in damage to the chromosomes, mutations of critical target genes, or altered hormone status.
Susceptibility: Biological markers of susceptibility identify individual differences in the body's response to environmental agents. Markers of susceptibility can include genetic traits, pre-existing disease that may increase the amount of an agent absorbed or the target tissue response, differences in metabolism, variations in immunoglobulin levels, or the capacity of an organ to recover from environmental insult.

Methods

General: Biomarkers may be able to provide early warnings of disease and patient response to therapies. Some of the techniques used to identify and measure biomarkers are listed below. Other methods are used to correlate a biomarker to a known disease.
Targeted mass spectrometry: A system based on targeted mass spectrometry, a technique that determines the makeup of molecules and their fragments, has been developed to accelerate the discovery of potential biomarkers. The system has helped develop protein biomarker panels for cardiovascular disease by screening blood samples. This system detects signals from specific chains of amino acids called peptides to produce peptide profiles that substitute for the protein candidates of interest.
Toxicogenomics: Genetic biomarkers are being used as tools to investigate drug toxicity. By determining how certain drugs interact with genes, gene-expression profiles, which identify which genes are switched on and which are switched off, can help distinguish between toxic and nontoxic drugs. Special gene-expression profiling technology can identify a variety of toxicity issues in short-term toxicologic studies. These methods may detect toxic changes earlier than conventional methods. This allows for an improved selection of candidates for drug development.
Identifying clinical use: Wegener's granulomatosis (WG) is a disease in which the blood vessels are inflamed. Scientists have developed a method to identify biomarkers that are useful in the diagnosis of WG. This method uses gene-expression profiling, which consists of gene-expression profiles from more than 8,700 human, rat, and mouse samples stored in more than 1,600 groups. This system holds detailed descriptions of disease manifestation from diseased and normal samples that are relevant to key disease treatment areas. The biomarker Arg 1 and other presumed biomarkers were identified with this system, for example, because proteins involved in the WG disease process reliably reduce blood levels of ARG 1.
Molecular signatures: A biomarker panel provides a more sensitive and compelling picture of a disease process than a single biomarker. Microarrays, for example, allow the rapid analysis of the expressions of large numbers of potential genetic biomarkers in a single experiment. This information can be used to explore genetic causes and the diagnosis of human disease. Of the three types of samples used to construct DNA microarrays, two are genomic (related to genes and their functions) and the third measures the levels of messenger RNA, a molecule that directs protein production. These samples are distinguished by the type of DNA used to generate the array and the type of information obtained.
DNA sequencing is a very promising technology for the development of predictive genetic biomarkers. 454 SequencingTM is a method that detects cancer mutations present at low levels. This method can generate hundreds of thousands of rapid and comprehensive DNA sequences in one test to detect cancer-associated genetic mutations.
Tumor biopsies contain a complex mix of cells that may possess different mutations. Some of these mutations could be responsible for making the tumor cells more vulnerable to chemotherapy, while other mutations could make the cells resistant to drug therapy. Identifying these biomarkers could help tailor targeted therapies.

Research

General: Currently, biomarkers are frequently used in the research and treatment of cancer. This is because cancer treatment requires the routine sampling of tissue through biopsy and surgical removal, and because biotechnology and drug companies are very active in the discovery and development of cancer drugs. Other diseases and conditions for which genetic biomarkers have been used include hepatic fibrosis, migraine headache, Huntington's disease, precancerous digestive tract lesions, vulnerability to drug side effects and genetic damage from environmental pollutants, and sensitivity to radiation therapy response.
Genetic biomarkers may provide a tool to predict individual patient response to drug therapy regimens, allowing more precise and effective treatment. Several therapeutic areas are the subject of ongoing investigation. Below are some diseases and disorders that are studied with genetic biomarkers.
Bladder cancer: Researchers have found inherited variability in a gene that provides instructions for making glutathione S-transferase M1 (GSTM1), which is an enzyme that detoxifies environmental carcinogens, including some contained in cigarette smoke. The GSTM1-null genotype is associated with a significantly increased risk for the development of bladder cancer. The same biomarker of effect also predicts increased cancer risk from other behaviors such as eating char-grilled meat.
Renal and non-small cell lung cancer: Two biomarkers of susceptibility may help monitor the effectiveness of treatment with the drugs sunitinib or bevacizumab for kidney and non-small cell lung cancer. Three potential biomarkers were measured during sunitinib or bevacizumab treatment. During treatment with sunitinib, increases in the candidate circulating endothelial progenitor cell (ccEPC) were parallel to the rise in blood VEGF (a protein targeted by sunitinib) levels. Levels of ccEPC decreased during the two-week period during which individuals were not receiving sunitinib.
Researchers found a noticeable difference in the change in ccEPC and VEGF levels after two weeks of treatment between patients with clinical benefit and those with progressive disease. An increase in ccEPCs was associated with a longer period without disease progression, which suggests that increased ccEPCs in cancer patients is unrelated to plasma VEGF levels.
DNA repair: Biomarkers can also detect an inability to repair DNA damage. DNA excision repair, the process by which damaged DNA is repaired, is highly variable among individuals. Problems with DNA excision repair can create a vulnerability to cancer. XPD 312Asn and XPD 751Gln are variant genes associated with a problem in the repair of ultraviolet light damage, making them biomarkers of susceptibility.
Skin cancer: Xeroderma pigmentosum (XP) is an inherited disease that makes a person highly sensitive to ultraviolet light and more than 2,000 times more likely to develop skin cancer. The disease is correlated with mutations in specific XP genes, which predict severe hypersensitivity ultimately resulting in skin cancer from sun exposure. People with XP have a defective nucleotide-excision repair (NER) system. Therefore, they are not able to repair damage caused by sunlight. By studying the genetic sequences involved in sensitivity to ultraviolet light and DNA repair in XP, researchers now have a better understanding of NER genes as biomarkers of susceptibility.
Breast cancer: Scientists have identified the location in the human genome of a gene for inherited breast cancer. The alteration in the defective gene is confined to a specific amino acid. Roughly 80% of women with this faulty gene copy, the p53 tumor-suppressor gene, develop breast or ovarian cancer. This makes the gene a biomarker of effect.
In addition, scientists have discovered a group of seven genes that cause drug resistance and aggressiveness in estrogen receptor-positive (ER+) breast cancer, which is the most prevalent form of breast cancer.
Use of a technique to identify gene function, the functional screen, led to the identification of several genes that comprise a new class of genes, the breast cancer anti-estrogen resistance (BCAR) genes. These genes are linked to resistance to tamoxifen, which is a form of hormonal therapy for breast cancer. As biomarkers of susceptibility, these genes may provide therapeutic targets for personalized treatment of breast cancer and disease prevention.
Childhood neuroblastoma: The gene that provides instructions for making ornithine decarboxylase (ODC1) is driven by the MYCN oncogene, a gene capable of causing a normal cell to change into a cancerous cell. This biomarker of effect is highly associated with aggressive tumor growth, poor prognosis, and death from this disease. Inhibition of ODC1 was shown to delay or prevent death in animals with this disease and represents a target for therapies in humans.
Colon cancer: For people who inherit a vulnerability to colon cancer, six or more oncogenes are needed to generate the tumors. MSH2 is a newly discovered gene that helps ensure the integrity of DNA duplication. When mutated, MSH2 creates a flaw in the DNA repair system, resulting in the production of oncogenes. MSH2 is located on chromosome 2. This biomarker of effect allows the accumulation of enough random mutations to produce a tumor.
Other: Biomarkers have been detected for many conditions in addition to cancer. These include B-type natriuretic peptide as a biomarker of effect for septic shock, neutrophil gelatinase-associated lipocalin as a susceptibility biomarker for contrast-induced nephropathy in children, plasma N-terminal-pro-B-type natriuretic peptide as a biomarker of effect for heart failure, sublining CD68+ macrophages as a biomarker of susceptibility to drug treatment for rheumatoid arthritis, and albumin as a biomarker of exposure to organophosphorus pesticides.

Implications

Genetic biomarkers have several potentially useful applications in both clinical medicine and drug development. They can help determine the safest and most effective treatment for patients, assist in providing a more accurate optimal drug dosage for individual patients, help identify individuals more likely to experience drug side effects, and assist in more efficient drug development by identifying disease subgroups and their molecular makeup. In addition, genetic biomarkers have the potential to provide more accurate cancer staging, monitoring of treatment effectiveness, and detection of disease recurrence.

Limitations

Measurement variability, such as laboratory error, is a concern because this can compromise the predictive validity of the biomarker.
Biomarkers are not 100% accurate in the prediction of disease risk or treatment response and can indicate only an elevated risk of disease or an increased or decreased chance of drug effectiveness.

Future research

An evolving trend in genetic biomarker research involves isolating biomarkers with gene and protein expression to predict metastatic cancer recurrence, diagnosis, and classification.
The predictive importance of circulating DNA in the bloodstream and its genetic alterations represents another area of future research focus.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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