DNA, what pangenomics will tell us and how genetic tests for tumors work

June 22, 2000. A fundamental date in the history of genetics: the Genome Bioinformatics Group of the University of California Santa Cruz, composed of Jim Kent, Patrick Gavin, Terrence Furey and David Kulp completes the Human Genome Project (Human Genome Project, HGP), an international scientific research project whose main objective was to determine the sequence of nitrogenous base pairs that form DNA and to identify and map the genes of the human genome from both a physical and functional point of view.

From that moment and in the years immediately following, medical-scientific research has made enormous and progressive steps forward development of innovative drugs that could selectively “target” only tumor cells. And great results have been achieved in the fight against cancer. Because “taking” exact aim thanks to genetic tests on tumor cells appropriate treatments can be offered to each patient.

The most classic example is that of the “Jolie” gene. Thanks to genetic research and the increased risk defined in a small section of the genetic heritage, it can be identified a specific genetic defect (the alteration of the BRCA1 and BRCA2 genes) and therefore indicate the most suitable treatment for each woman on a case-by-case basis. But more and more, and for different types of tumors, we find conditions written in the DNA capable of directing treatments, with cost savings for health systems and with greater precision (and often also a greater quality of life, in addition to improvement in survival) for the patient.

To each his own therapy it is therefore no longer just a dream. But a reality. Which must always be guided by the doctor, to identify the tests that are really needed. Given that we are getting ever closer to the growth that was expected in 2020 for this market, when we imagined in the next four to five years a turnover destined to exceed 17 billion dollars on genetic tests and 35 billion for the broader sector which sees genomics and services are also implicated. Double-zero growth, in short, with a tendency towards an increasingly significant increase and not only to identify diseases but also to take care of them as best as possible based on the characteristics of the cells. In short: we go beyond what already seemed like a dream achieved with the end of the Human Genome project. And now, it appears increasingly important to integrate information on a global scale. On this front, research will say more and more in the future. Thanks to pangenomics, which “cross-references” data on different populations. To reveal new secrets of DNA and develop increasingly tailor-made treatments.

What pangenomics is and what it will bring

Pangenomics represents an approach that could lead to a new concept of public health and technological hospital, where therapeutic choices could also be based on the genomic structure of the individual patient. It aims to increase information on the individual genome for a truly personalized medical approach, influencing the treatment but also the prevention of diseases. A genome is the set of instructions that DNA uses for every living creature to develop and function.

“Genome sequences differ slightly between individuals. In the case of humans, Two people's genomes are, on average, more than 99% identical.. Small differences contribute to the uniqueness of each person and can provide information on their health, helping to diagnose a disease, predict outcomes and establish medical treatments – explained Marco Seri, Scientific Director of IRCCS University Hospital of Bologna, Policlinico of Sant'Orsola on the occasion of a public meeting organized by the Academy of Sciences at the Johns Hopkins University in Bologna. To understand these genomic differences, it is necessary to have a reference human genome sequence to use as a standard. The original human reference genome sequence is almost 20 years old and has been regularly updated as technology has brought new knowledge. However, its contribution may be limited in representing the diversity of the human species, since it consists of genomes from only about 20 people and the majority of the reference sequence, about 70%, comes from a single person, an American with European ancestry and African. The new 'pangenome' includes the genome sequences of 47 people from Africa, Asia, the Americas and Europe, and the researchers' goal is to increase the genome sequences to 350 people. Since everyone has a unique genome, using a reference genome based predominantly on a single person can lead to inequalities in genomic analyzes altering the interpretation and consequently, for example, the prediction of a genetic disease. In other words, in this way it will be possible to have available to each individual a complete map of their critical issues, and of all their specificities in reacting”.

But our National Health System would be able to cover the costs of this new vision? “If on the one hand we must take into consideration the costs linked to the production and conservation of the data – concludes Seri – on the other we should consider the savings due both to the reduction of costs linked to inappropriate therapies and to those inherent to often very long diagnostic procedures. Furthermore, we must consider the savings for hospitalizations and ongoing care of those patients suffering from complex and/or chronic pathologies that could have been prevented.”

Why the DNA of populations is important

Like Indiana Jones of DNA, in recent years scientists have aimed to recognize the population at high risk or perhaps protected for certain diseases, to study their genetic material and bring it to the operations center of large research facilities. In this way we aim to identify the good or bad genetic predispositions to guide the development of tailored medicines.

This is what happened for example in Iceland, where people are very similar, with blue eyes and blond hair. A sort of invisible “stigmata” that is invariably transmitted from generation to generation, and seems to bring back, going back in time, the characteristics of the legendary leader Erik the Red. This situation derives from the fact that the island remained distant from the rest of civilization for centuries, and therefore there were no migratory flows capable of modifying the genetic structure of the population. But it's not enough.
In New Guinea some geneticists some time ago a few years ago went so far as to study the Hagahai tribe, which lives on the highlands, to understand why these indigenous people are naturally immunized against a special leukemia virus, very similar to that of AIDS.
And also the Hopi tribe, in Arizona, has characteristics that make it important for the study of albinism. All without forgetting the research conducted in Tristan de Cunha, which is part of the most remote archipelago in the world, amidst the storms of the South Atlantic. Some time ago, noticing that many people suffer from asthma, the genetic origin of the phenomenon was investigated. It could all trace back to an English non-commissioned officer, William Glass, who commandeered the islands in the early 1800s.

The different mutations in DNA

When talking about cancer and genetic tests, clarity is needed, especially in terms of the approach towards family members of individuals with the disease. Generally, therefore in the majority of cases, the tumor arises from mutations that arise during the person's existence, therefore they are not “written” in his DNA but they directly affect some cells. These are defined somatic mutations. Their existence is limited to the individual subject and therefore cannot be transmitted.
The situation is different when it comes to germline mutations. In this case, DNA alterations are present from birth and can be the basis of a lower number of tumors, calculated at approximately 5-10% of the total. These mutations, being part of the subject's genetic makeup since birth, can obviously be passed on to children. They increase the risk of developing tumors and for this reason doctors, based on the type of tumor identified, can proceed to evaluate the situation in the family.

An example: breast cancer, when and to whom should you propose the test?

After a systematic review of the scientific literature, the recommendations of the scientific society ASCO together with the Association of American Breast Surgeons were published in the Journal of Clinical Oncology.
“From reading the study, important news emerges on the use of genetic tests – explains Emanuela Lucci Cordisco, medical geneticist and researcher at the Catholic University of Rome and medical director at the IRCSS Gemelli Polyclinic in Rome. First, American oncologists wanted to answer a fundamental question: Who should you propose the test to? The recommendations indicate that genetic blood testing should be offered to the highest number of people newly diagnosed with breast cancerespecially women up to 65 years of age and not until the age of 40 as happens today in Italy. In fact, the importance of offering personalized clinical management to the patients who present was underlined alterations of the BRCA1 and BRCA2 genes for whom the use of a drug is able to provide a therapeutic advantage”.

This is why the test should be offered to the greatest number of people. People over the age of 65 or with older diagnoses should also have access to genetic testing if this is important for their clinical management. Finally, in some cases it could also be useful to propose the analysis of other genes.

“This is an ever-increasing number of people: our opinion is that if in our country too a such a massive number of tests it will be necessary to find a fair compromise between the increase in the age threshold and the workload of the laboratories – continues the expert. This aspect indicated by ASCO raises the need for reflection at a European level and in each individual country to verify the possibility of applying these large numbers depending on the peculiarities of the different national healthcare systems.”

How to propose the test

When the germline genetic test is proposed, i.e. on the blood, it is necessary to make sure all the implications are understood. The informed consent required requires the signature of the patient who must have clearly understood the scope of the test; for this reason a counseling for the pre and post genetic test, as highlighted by ASCO. In pre-genetic counseling the implications of the test, the possible results, its limits and clinical usefulness must be shared with the personal and family implications. In the post-test counseling the results, the risks associated with them, the prevention methods and indications for family members must be discussed.

“It is very important to discuss the outcome of the genetic test for hereditary predisposition which also defines the risk for family members. And what the geneticists of the Italian Society of Human Genetics (SIGU) remember. It is very important that patients understand all these implications in order to pass on the instructions to their families. But be careful. With massive use of oncological tests Many more geneticists trained in oncology will be neededwhich also deepen their knowledge of the therapies available today in a continuous updating process.