Definition

A biomarker that indicates the potential for developing a disease or medical condition in an individual who does not currently have clinically apparent disease or the medical condition.

Examples

• BReast CAncer genes 1 and 2 (BRCA1/2) mutations may be used as a susceptibility/risk biomarker to identify individuals with a predisposition to develop breast cancer (Struewing et al. 1997; Thorlacius et al. 1998).
• Factor V Leiden may be used as a susceptibility/risk biomarker to identify individuals with a predisposition to develop deep vein thrombosis (DVT) (Kujovich 2011).
• Apolipoprotein E (APOE) gene variations may be used as susceptibility/risk biomarkers to identify individuals with a predisposition to develop Alzheimer’s disease (Chartier-Harlin et al. 1994; Genin et al. 2011).
• Infection with certain human papillomavirus (HPV) subtypes may be used as a susceptibility/risk biomarker to identify individuals with a predisposition to develop cervical cancer (Khan et al. 2005; Schiffman et al. 2011).
• C-reactive protein (CRP) level may be used as a susceptibility/risk biomarker to identify adult patients with a greater likelihood of incident coronary disease (Greenland et al. 2010; Pearson et al. 2003; Ridker et al. 2007; Ridker et al. 2008).
• Urinary concentration of tobacco specific nitrosamines (TSNAs) (e.g., total N-Nitrosonornicotine (total NNN) and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL)) may be used as susceptibility/risk biomarkers to identify those at greater likelihood of cancer development (Hecht 2002; Hecht et al. 2008; Khariwala et al. 2013; Yuan et al. 2011; Park et al. 2015; Nilsson 2011; U.S. Department of Health and Human Services 2014, Yalcin and de la Monte 2016).

Explanation

A susceptibility/risk biomarker is a biomarker that is associated with an increased, or in some cases, decreased chance of developing a disease or medical condition in an individual who, from a clinical standpoint, does not yet have that disease or medical condition. An example of a susceptibility/risk biomarker is a genetic biomarker that indicates whether an individual has an increased likelihood of developing cancer later in life. This is in contrast to prognostic biomarkers, which indicate an increased likelihood of a specific clinical event in an individual already diagnosed with a disease or medical condition, and diagnostic biomarkers, which may confirm whether a disease is actually present. Susceptibility/risk biomarkers may be detected many years – in some cases decades – before the appearance of clinical signs and symptoms. Susceptibility/risk biomarkers do not describe a relationship to any specific treatment.

A familiar example of a susceptibility/risk biomarker is elevated low-density lipoprotein (LDL) cholesterol levels, which identify an increased risk of coronary artery disease. Virtually all cardiovascular risk models include LDL cholesterol to estimate the likelihood of having a cardiovascular event by some future time point. Additional factors such as high-density lipoprotein cholesterol levels, diabetes, age, sex, smoking status, and family history are also routinely considered in models of risk to improve the accuracy of the predictions.

The main utility of susceptibility/risk biomarkers in clinical practice is to guide preventive strategies. A susceptibility/risk biomarker like BRCA1/2 mutation is used to evaluate the likelihood of developing breast and ovarian cancers. Such biomarkers may be used to determine whether lifestyle, nutritional, or other preventive interventions are indicated. Susceptibility/risk biomarkers may also identify individuals for whom more aggressive surveillance for the presence of disease is needed, such as more frequent colonoscopy or mammography to screen for cancers. The utility of a susceptibility/risk biomarker depends in part on whether there are interventions available to modify risk of disease.

In a medical product development setting, susceptibility/risk biomarkers may be useful for clinical trial enrichment, in the same way that prognostic biomarkers would be used. Often, in a primary prevention setting, it is very difficult to accrue enough clinical events to make clinical trials feasible. Enriching preventive clinical trials for those patients who are most likely to develop a particular disease may therefore be necessary, particularly for the evaluation of chemoprevention therapies or targeted use of vaccines. This allows for 1) the trial to be feasibly conducted by enriching for a population that may be more likely to develop the disease or medical condition and 2) preventive interventions with potential side effects to be appropriately targeted to strike the right balance of benefit and risk.

Susceptibility/risk biomarkers share many properties with prognostic biomarkers insofar as they indicate risk for some future occurrence of a disease-related event. However, the main distinction is that prognostic biomarkers are used in individuals who already have been diagnosed with a particular disease, while susceptibility/risk biomarkers could be used in individuals who otherwise appear healthy. The line distinguishing these types of biomarkers may not be so clear in some instances. For example, a susceptibility/risk biomarker and a prognostic biomarker could forecast the same event, i.e., a myocardial infarction. However, in this example, atherosclerosis begins to develop early in life. The point at which an individual is “diagnosed” as having a disease is more a function of developing clinically overt signs and symptoms (e.g., angina). Regardless, the screening or intervention strategies could differ between someone who appears healthy and someone who has established coronary artery disease.

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