Biomarkers in Clinical Medicine Xiao-He Chen, Shuwen Huang, and David Kerr
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UNIT 4. INTEGRATION OF BIOMARKERS INTO EPIDEMIOLOGY STUDY DESIGNS CHAPTER 17. Biomarkers in clinical medicine Xiao-He Chen, Shuwen Huang, and David Kerr Summary Introduction Biomarkers have been used in disease severity, and 5) prognostic Health sciences have been clinical medicine for decades. With biomarkers to predict future disease experiencing a shift from population- the rise of genomics and other course, including recurrence, based approaches to individualized advances in molecular biology, response to therapy, and monitoring practice. The focus on individuals biomarker studies have entered a efficacy of therapy (1). Biomarkers could make public health strategies whole new era and hold promise can indicate a variety of health or more effective by allowing for early diagnosis and effective disease characteristics, including practitioners to direct resources treatment of many diseases. A the level or type of exposure to towards those with the greatest biomarker is a characteristic that is an environmental factor, genetic need. However, the success of objectively measured and evaluated susceptibility, genetic responses to these efforts will largely depend UNIT 4 as an indicator of normal biological environmental exposures, markers on the continued identification processes, pathogenic processes of subclinical or clinical disease, or of biomarkers that reflect the or pharmacologic responses to a indicators of response to therapy. individual’s health status and risk 17 CHAPTER therapeutic intervention (1). They This chapter will focus on how at key time points, and successful can be classified into five categories these biomarkers have been used integration of these biomarkers into based on their application in different in preventive medicine, diagnostics, medical practice. To be clinically disease stages: 1) antecedent therapeutics and prognostics, useful, tests for biomarkers must biomarkers to identify the risk of as well as public health and their have high predictive accuracy, developing an illness, 2) screening current status in clinical practice. and be easily measurable and biomarkers to screen for subclinical reproducible, minimally invasive, disease, 3) diagnostic biomarkers and acceptable to patients and to recognize overt disease, 4) physicians (2). Once a proposed staging biomarkers to categorise biomarker has been validated, it Unit 4 • Chapter 17. Biomarkers in clinical medicine 303 can be used to assess disease risk level has been used as a marker in of the TYR gene that encodes a in a general population, confirm investigating adolescents’ cigarette R402Q amino acid substitution, diagnosis of disease in an individual consumption. A biomarker of effect previously shown to affect eye patient, and tailor an individual’s is a measurable alteration of an colour and tanning response, was treatment (choice of drug treatment endogenous factor that is shown associated with increased risk of or administration regimes). In to be linked with impairment or developing cutaneous melanoma evaluating potential drug therapies, disease resulting from exposure to (CM) and basal cell carcinoma a biomarker may be used as a an exogenous agent. For example, (BCC); 2) variations in a haplotype surrogate for a natural endpoint, such the alteration in pulmonary function (set of closely associated genes) as survival or irreversible morbidity. tests in children after exposure to near the ASIP gene, known to If a treatment alters the biomarker, environmental tobacco smoke is affect pigmentation traits, conferred which has a direct connection to a biomarker of effect (3). Somatic significant risk of CM and BCC; and improved health, the biomarker mutations have been used as 3) an eye colour variant in gene serves as a surrogate endpoint for biomarkers of effect after exposure TYRP1 was also associated with evaluating clinical benefit. More to carcinogens. A biomarker of risk of CM (5–7). The relationship recently, with rapid advances susceptibility indicates individual between these biomarkers and their in the molecular approaches to factors that can affect response to relationship with clinical medicine biology, genetics, biochemistry and environmental agents. These reflect are illustrated in Figure 17.1. medicine, and in particular with the variations between individuals There are two layers of exposure rise of genomics, transcriptomics, in genetic structure, some of and effect biomarkers. The first proteomics and metabolomics, which make the individual more represents hazardous exposures molecular biomarkers appear to susceptible to health effects from to a healthy human body that could hold the promise of transforming environmental exposures (4). For cause negative biological effects medical practice into personalized example, skin cancer is related to (e.g. functional changes, somatic medicine—the right treatment at the excessive sun exposure, but not mutations) and eventually cause right dose for the right person at the everyone develops skin cancer even disease. Another layer indicates right time for the right outcome. with the same amount of exposure. treatment exposures to a diseased Three recent studies revealed human body that could induce Context and public health that genetic variants associated positive biological effects and lead significance with three sections of genes were to the improvement of conditions found to be linked with increased or to the complete recovery from Clinical medicine covers disease risk of skin cancer: 1) the variant disease. Susceptibility biomarkers prevention, diagnosis and treatment. Biomarkers play a critical Figure 17.1. Simplified flowchart of classes of biomarkers (indicated by boxes) role in all these aspects. There are representing a continuum of changes. Solid arrows indicate progression, if it occurs, to the next class of marker. Dashed arrows indicate that individual biomarker three major types of biomarkers: influences and/or indicates the rates of progression biomarkers of exposure, effect and susceptibility. A biomarker of exposure is an exogenous chemical or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism. Specific markers of exposure include the presence of a xenobiotic compound or its metabolites in body tissues or fluids and in excretory products. For example, blood lead concentration has been used as a marker for lead exposure; saliva cotinine (a metabolite of nicotine) Source: Adapted from (106) 304 are present in every step of the preventive medicine for several and activating mutation in Ras process. For example, some decades to: screen before birth for oncogene and loss of function individuals exposed to air pollutants genetic disorders, such as Down mutations in APC and p53 tumour show severe biological effects and syndrome; screen newborn babies suppressor genes for colon cancer) manifest disease symptoms, while for genetic diseases, such as (12). Subtypes of these cancers and others experience little or no effect. phenylketonuria (PKU) (9); check most other common diseases are The same discrepancy appears with whether an individual is a carrier less deterministic; even apparently drug treatment. While some patients for a recessive disorder (where simple Mendelian disorders may benefit and are cured, others show abnormal genes must be inherited prove to have widely variable no effect from treatment or develop from both parents to lead to the clinical phenotypes. For example, severe side-effects or die. In clinical condition), such as cystic fibrosis; thalassaemia, an apparently simple medicine, the first layer is more and indicate whether someone genetic disease, has substantial related to disease prevention and with a family history of a late-onset complexities (13). Individuals with diagnosis, while the second layer is disease, such as Huntington’s, exactly the same globin mutations more relevant to disease treatment is likely to develop the disease. may suffer either from a severe life- and recovery. These tests are aimed largely at threatening disorder or be relatively single-gene disorders that have unaffected. Despite this, great Biomarkers in preventive Mendelian patterns of inheritance. efforts have been made towards medicine The identification of genetic variants simultaneous, systematic analysis responsible for diseas, in these of larger numbers of biomarkers Preventive medicine aims to promote single-gene disorders can lead for disease prediction, although and preserve health and longevity directly to clinically helpful and these approaches are more suited in individuals and populations, use reasonably accurate predictions to research than routine diagnostic epidemiological approaches to and diagnosis of disease. Early activity. Biomarkers may help predict define high-risk groups, prevent and diagnosis and proper treatment those individuals more susceptible to limit disease and injury, facilitate can make the difference between common disorders, so that specific early diagnosis through screening lifelong impairment and healthy attention can be directed towards and education, enhance quality of development. them (e.g. enrolment in a screening the health care system and improve Common, complex diseases programme). However, translating quality of life. To realize these aims, such as cancer, heart disease and these biomarkers into clinical medical practitioners need the diabetes contribute to the major medicine to help prevent people proper tools