A gene signature or gene expression signature is a single or combined group of genes in a cell with a uniquely characteristic pattern of gene expression that occurs as a result of an altered or unaltered biological process or pathogenic medical condition. This is not to be confused with the concept of

gene expression profiling In the field of molecular biology, gene expression profiling is the measurement of the activity (the gene expression, expression) of thousands of genes at once, to create a global picture of cellular function. These profiles can, for example, dis ...

. Activating pathways in a regular physiological process or a physiological response to a stimulus results in a cascade of

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

and interactions that elicit altered levels of gene expression, which is classified as the gene signature of that physiological process or response. The clinical applications of gene signatures breakdown into prognostic, diagnostic and predictive signatures. The phenotypes that may theoretically be defined by a gene expression signature range from those that predict the survival or prognosis of an individual with a disease, those that are used to differentiate between different subtypes of a disease, to those that predict activation of a particular pathway. Ideally, gene signatures can be used to select a group of patients for whom a particular treatment will be effective.

Timeline of gene signature detection

In 1995, 2 studies conducted identified unique approaches to analyzing global gene expression of a genome which collectively promoted the value of identifying and analyzing gene signatures for physiological relevance. The first study reports a technique that improves expressed sequence tag (EST) analysis, known as Serial Analysis of Gene Expression (SAGE) that hinged on sequencing and quantifying mRNA samples which acquired levels of gene expression that eventually revealed characteristic gene expression patterns. The second study identified a technique that is now widely known as the

microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...

which quantifies complementary DNA (cDNA) hybridization on a glass slide to analyze the expression of many genes in parallel. These studies drew greater attention to the wealth of information that analysis of gene signatures bear that may or may not be physiologically relevant. Pressing forward, the latter technique has revolutionized research in genetics and DNA chip technology as it is a widely adopted technique to profile gene expression signatures such that these physiological responses can be cataloged in repositories such a
NCBI Gene Expression Omnibus
This catalogue of prognostic, diagnostic and predictive gene expression signatures allow for predictions of onset of pathogenic diseases in patients, tumour and cancer classification, and enhanced therapeutic strategies that predict the optimal target candidates subjects and genes. Today, microarrays and other quantitative methods such as

RNA-seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...

that encompass

, are moving towards promotion of re-analysis and integration of the large, publicly available database of gene expression signatures and profiles to uncover the full threshold of information these expression signatures hold.

Types of gene signatures

Prognostic gene signature

Prognostic refers to predicting the likely outcome or course of a disease. Classifying a biological phenotype or medical condition based on a specific gene signature or multiple gene signatures, can serve as a prognostic biomarker for the associated phenotype or condition. This concept termed prognostic gene signature, serves to offer insight into the overall outcome of the condition regardless of therapeutic intervention. Several studies have been conducted with focus on identifying prognostic gene signatures with the hopes of improving the diagnostic methods and therapeutic courses adopted in a clinical settings. It is important to note that prognostic gene signatures are not a target of therapy; they offer additional information to consider when discussing details such as duration or dosage or drug sensitivity etc. in therapeutic intervention. The criteria a gene signature must meet to be deemed a prognostic marker include demonstration of its association with the outcomes of the condition, reproducibility and validation of its association in an independent group of patients and lastly, the prognostic value must demonstrate independence from other standard factors in a multivariate analysis. The applications of these prognostic signatures include prognostic assays for

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

leukaemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and are continually being developed for other types of cancers and disorders as well.

Diagnostic gene signatures

A diagnostic gene signature serves as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

that distinguishes phenotypically similar medical conditions that have a threshold of severity consisting of mild, moderate or severe phenotypes. Establishing verified methods of diagnosing clinically indolent and significant cases allows practitioners to provide more accurate care and therapeutic options that range from no therapy, preventative care to symptomatic relief. These diagnostic signatures also allow for a more accurate representation of test samples used in research. Similar to the procedure of validation of prognostic gene signature, a criterion exists for classifying a gene signature as a biomarker for a disorder or diseases outlined by Chau et al.

Predictive gene signatures

A predictive gene signature is similar to a predictive biomarker, where it predicts the effect of treatment in patients or study participants that exhibit a particular disease phenotype. A predictive gene signature unlike a prognostic gene signature can be a target for therapy. The information predictive signatures provide are more rigorous than that of prognostic signatures as they are based on treatment groups with therapeutic intervention on the likely benefit from treatment, completely independent of prognosis. Predictive gene signatures addresses the paramount need for ways to personalize and tailor therapeutic intervention in diseases. These signatures have implications in facilitating personalized medicine through identification of more novel therapeutic targets and identifying the most qualified subjects for optimal benefit of specific treatments.

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