From genome analysis to personalized medicine

Genes are the functional and physical units of heredity that pass from parent to offspring. Genes are made up of segments of DNA (deoxyribonucleic acids), with each segment providing a blueprint (the genetic code) for a cellular component. When a gene is ‘expressed’ in a cell, a copy of the DNA is generated into RNA (ribonucleic acids). This RNA now holds the information to make a specific protein or to be used directly in other cellular structures.

Much has been said about mapping the human genome and, perhaps, one of the most frequently perceived reasons for this work is to enable us to use genetic testing as a way of looking for abnormalities (mutations) that are linked to a disease or disorder. However, gene expression profiling i.e. creating a specific profile of the genes that are actively being expressed in a cell or tissue provides us with an extremely powerful tool for the diagnosis, prognosis and therapeutic responsiveness of a disease state – and, even more significantly, this information relates to the individual patient. Gene expression profiling leads us one step closer to truly personalized medicine.

Combining knowledge and technologies

Many thousands of genes are being expressed within the cell at any one time, only some will determine the behavior of a specific tumor. Focusing on the information carrier (RNA), Agendia builds up a profile of active genes that are relevant to a particular type of tumor i.e. a gene expression profile that is clinically-relevant. Once validated, this profile can be incorporated into a commercially available test.

Knowledge of a tumor's gene expression profile can, for example, be used to identify the site of origin in cases where the location of the primary tumor is unknown, to predict the ability of an individual tumor to spread or to predict a tumor’s response to anti-cancer drugs. In these examples, the information obtained enables physicians to determine the best course of treatment for an individual patient, thereby avoiding over- or under-prescribing potentially harmful anti-cancer drugs, and enables drug developers to differentiate between responders and non-responders when setting up clinical trials.

The leaders of Agendia are the inventors and initiators of in vitro diagnostic microarray testing - the technology which forms the basis for their commercially available tests.

A DNA microarray is a collection of microscopic DNA spots, commonly representing single genes, arrayed on a solid surface by covalent attachment to a chemically suitable matrix. The array format enables the expression levels of thousands of genes to be monitored simultaneously. RNA will readily hybridize (bind) with ‘matching’ DNA segments on the microarray. This hybridization can be detected and quantified using a highly sensitive fluorophore (a molecule that fluoresces only when hybridization occurs).

In the Agendia tests, an array is prepared to enable quantification of the expression of specific genes of interest. For this purpose, the RNA from a tumor sample will hybridize with these DNA spots only if the gene is being actively expressed in the tumor. Hence the gene expression profile for the specific tumor can be determined.