Methods and procedures in genomic testing for precision medicine

We have talked a lot in previous articles about genomic testing and its importance in the revolution of personalized precision medicine. But what are they? What exactly are we talking about?

Genomic tests, sometimes also called genetic tests if we are talking about the study of inherited diseases, are those that sequence (“read”) the patient's genome, or a part of it, to identify biomarkers; i.e. specific signals within that genomic sequence, that are related to diseases.

How useful is this? Well, knowing the presence or absence of these biomarkers can help doctors to detect the risk of suffering from certain diseases, such as hereditary diseases, or the specific genetic variation related to a disease that is already being suffered, as in the case of oncological diseases.

Genomic tests sequence the genome to identify biomarkers that help detect risks for certain diseases.

In this last case, knowing which mutation or genetic variation is causing the cancer will help the physician to decide which treatment has the best chance of success, thus personalizing the therapy to the patient.

In this article we will find out what genomic tests are, what they mean for us as patients, and what are the most common types of tests.

What is genomic or genetic testing?

Genomic or genetic testing begins with taking a sample from the patient. In germline genetic testing or genomic testing, i.e., with markers present in all cells of the body, as in diseases inherited from the parents, samples are usually obtained from saliva or blood.

This is due to the ease of obtaining this type of sample, with minimally invasive procedures such as a blood draw or saliva swab extraction. Why is blood still used if DNA can be obtained from saliva by simply “swabbing” a swab?

Among other reasons, it must be taken into account that in the mouth we have an enormous amount of symbiont or commensal bacteria, which coexist with us and which have their own genetic material. Therefore, they can contaminate to some extent the result of the sequencing of that sample, lowering its quality.

Knowing which genetic mutation or variation is causing cancer will help the physician decide which treatment has the best chance of success, thus personalizing the therapy to the patient.

This does not mean that the results are useless, but for certain genetic markers that need to be detected with very high precision, the quality may not be high enough for the physician to consider the results as decisive.

In the case of looking for genomic variations not in the germline, but in the somatic line, the sampling process is slightly different. Somatic mutations are those inherent to oncological diseases, for example, since the biomarkers we are looking for will be found in some cells of the body and not in others.

That is to say, in a tumor cancer, for instance, we will look for the mutation or genomic variation in the tumor cells (“diseased”) in relation to the rest of the body cells (“healthy” or control cells). We will then normally need two samples, one as described above from saliva, or healthy tissue, and another from the tumor biopsy. This process is invasive and, depending on the patient's state of health and the location of the tumor, can be dangerous.

Transforming biological samples into data

There are liquid biopsies to minimize these risks, in which, through a blood sample, circulating tumor DNA is located in the bloodstream. Although this type of biopsy is not currently useful for all oncological diseases, it is being researched and developed at a dizzying pace due to its enormous practical usefulness in improving the quality of care.

Samples are generally obtained from saliva or blood, due to the ease of obtaining this type of sample, with minimally invasive procedures.

Once the sample of interest has been obtained, the genetic material of interest (DNA or RNA) will be extracted and prepared for the chosen sequencing technique. The prepared sample will then be introduced into the so-called sequencers, which will be the machines in charge of converting these biological samples into data, into text.

This text will be used by the bioinformaticians to search for genetic variations compared to a reference sequence of a human genome, or of the control sample in the case of somatic mutations and give them meaning.

Those mutations that have clinical weight in relation to the test requested by the physician will normally be communicated to the physician through the production of a report. From this point on, it will be the specialist physician, who has or should have all the information concerning the patient, who will assess the value of these detected variations and make the best decisions for the patient's health.

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Genetic testing types for precision medicine

In this post we will focus on molecular tests related to the study of DNA sequencing. Apart from these, we can have other types of tests related to genetics within the world of precision medicine, including:

• Biochemical tests to measure protein activity.
• Expression tests to study which genes are activated.
• Chromosomal tests that look at changes in genetic material at the chromosomal level, on a large scale.

Molecular tests, which are those that look for the aforementioned genetic variations, include whole genome sequencing (WGS) and whole exome sequencing (WES) and targeted sequencing, as in panels.

Within healthcare practice, this translates into the following highlighted tests:

Neonatal screening

This is the most common genetic test; we are all familiar with the heel prick test.

Through this systematic test, newborns can be screened for the possibility of suffering from some type of genetic disease before the adults around them can see the symptoms.

■ It may be too late in diseases such as glutaric aciduria type I, by the time the baby shows symptoms, and can have lifelong consequences. On the other hand, if detected early, the onset of symptoms can be prevented “simply” by adjusting the diet.

Carrier screening or carrier-screening

This type of testing is often used to help future parents to know if they are carriers of certain diseases, thus knowing if there is a risk of transmitting them to their offspring.

■ These tests are performed on people who have a family history and therefore have a high chance of being transmitters of inherited diseases.

Prenatal diagnosis

These are tests performed on the fetus to detect early modifications in its genes and chromosomes, so that both physicians and parents can make an informed decision.

This type of test is performed, as before, in cases in which the parents may be carriers of hereditary diseases due to family history. However, given the universalization of these tests, they are also usually performed in pregnancies suspected of being at risk or that have presented some type of problem during their development.

■ In this case, the sample is obtained either by amniocentesis or by chorionic villus sampling (placental sampling).

Genetic predisposition testing

Panels sequence very specific parts of the genome as they target specific genes, which can be between one gene, or a few, to several thousand. They are used when it is known in which gene or genes the mutation should be sought.

The best-known case might be the breast and ovarian cancer panel, which includes the BRCA1 and BRCA2 genes as the main indicators of the risk of developing breast and ovarian cancer in the future. But these are not the only genes that may be involved in this type of cancer; most current tests already sequence around 30 genes.

Why perform a panel and not a WGS or WES? Well, because by reducing the size of the genetic material to be sequenced the technique is more cost-effective and the data produced are much easier for professionals to handle, so that waiting times for results are reduced.

■ These panels can be used both to determine genetic predisposition and to help determine patient treatment.

Conclusion

Genetic testing has revolutionized modern medicine by enabling early detection of inherited diseases and prediction of genetic predispositions. From testing for prospective parents, prenatal diagnostics to genetic predisposition panels, these tools provide key information to make informed and personalized health decisions.

The universalization and continuous improvement of these tests ensure that more and more people can benefit from more accurate and effective medical care.

Genetics thereby opens a window into the future of preventive and personalized medicine. With the development of more affordable and accurate tests thanks to digital technologies, more and more people will be able to know their risks and take proactive measures to maintain their health.

In addition, the integration of genetics into clinical practice is not only improving the diagnosis and treatment of diseases but also providing a more holistic and patient-centered approach.