The methylome, a new (epi)genetic identity card for cancers

Better understanding and treating cancer requires deciphering the workings of this disease – or rather these diseases, as it can take many forms.

One way in full development is to look at DNA. All of our cells (including tumor cells) have a DNA molecule in their nucleus: a sort of long text in which the genes and all the genetic information that helps define us are linked together.

Cancers result from modifications of this genetic text (we speak of mutations of its “sequence”) occurring in a cell, which can be particularly massive and lead to its uncontrolled multiplication. A tumor then develops which, as it grows and evolves, can invade the body.

Recent advances in “high-throughput” sequencing techniques (allowing the rapid reading of genetic text) have made it possible to identify the changes hiding behind many cancers. From now on, it is possible to list the “catalogue” of mutations of a tumor in order to establish its identity card: a considerable asset for better understanding the nature of the cancer in question, its origins, its internal workings and its prognosis. A better understanding of the disease contributes to the development of more effective treatments.

A second level of genetic information

But the genetic information is not located only in the text inscribed in our DNA… A second level of coding, called “epigenetic”, has been identified, the study of which has been developed in recent decades. Epigenetics is to genetics what punctuation is to a sentence: the meaning of a sentence will be different depending on the presence and location of commas, dashes or parentheses…

Epigenetic modifications (punctuation) of DNA (sentences) are thus able to influence the message coded in the DNA, and the way it is expressed.

From a chemical point of view, our “genetic commas” can take the form of adding (or removing) groups of specific atoms – in this case methyls (CH3). Reading this epigenetic “code” makes it possible to establish another type of identity card: the methylome.

There are several levels of information in DNA: the genetic text (written with the four “letters” A, T, C and G), which constitutes the genome, and the epigenetic modifications (in particular methylations) which modulate the original message.

Here again, its detailed study and its comparison with the methylomes of healthy and tumor cells are rich in information: if the reading of the genetic sequence (of the text) provides information on the mechanisms of exuberant growth of the cancerous cell, that of the methylome specifies the nature of cancer and its origin. In the endthe deciphering of these two levels of complementary data helps to better characterize cancer and to choose the most appropriate cancer treatments.

Pioneering use in neuro-oncology

If high-throughput sequencing techniques took off at the end of the 20e century, the study of the methylome clearly belongs to the XXIe century.

Due to its cost and the equipment needed to map DNA punctuation, this technique is currently only implemented in certain specialized medical oncology centres. In the clinic, it is especially in neuro-oncology (brain and spinal tumors), a pioneer in the field, that its use is the most successful – especially in cases of difficult diagnosis. L’World Health Organization (WHO) also recommends its study in the diagnosis of many brain tumors since 2021.

If other types of cancer (sarcomas, developed from bones, muscles, fat, etc.) are also beginning to be studied by their methylome, the results are still preliminary.

The analysis of methylome data relies on bioinformatics and requires the development of artificial intelligence (AI) algorithms (calculation formulas). The basic idea is simple: you have to classify together the tumors that have the same punctuation (therefore the same variations at the epigenetic level), like a game of 7 families where the player tries to bring together the individuals of the same family.

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A large database developed by a team from the University of Heidelberg already brings together the methylation profiles of nearly 100,000 brain tumorsclassified into 80 families or subfamilies.

Open access, it allows the sending of new data which is analyzed online for free. The advantage is twofold since on the one hand the software offers the pathologist a classification of the tumor sent, and the Heidelberg team enriches its database, making the AI ​​algorithms more efficient – in general, more a tumor analysis algorithm, the more reliable the classifications it offers. This form of international collaborative project thus benefits the greatest number: patients, doctors and researchers.

In some cases, the machine may prove to be better than the pathologist who traditionally examines cancer cells under a microscope. But if the machine can sometimes overtake the human, it can also be found wanting in the face of very rare tumors that it would not have (or hardly) encountered: the risk is then that it will not succeed in classifying the tumor or, more seriously, the class in a bad family. This is why any diagnosis is checked by a pathologist, who makes a summary of his microscopic diagnosis, the results of the methylome and the mutations detected by reading the genetic text.

Any final diagnosis is thus said to be “integrated” because it takes into account microscopic, genetic and epigenetic data. More reliable, it allows the oncologist to choose the best treatments.

Despite the limitations of AI, methylome analysis does indeed represent considerable progress in the diagnosis of brain tumours, particularly in children – in whom they are much more varied than in adults. In France, the leading neuro-oncology university hospital centers (CHU) are gradually being equipped so that, in the years to come, an epigenetic identity card can be established for each brain tumor (in addition to the genetic identity already made).

A technique that will gain even more power

Unlike the genetic text which is literally fixed in the egg, from our conception, and is very complex to modify, the epigenetic information is more “modifiable”. Some treatments called “epidrugs” can thus change the punctuation of the DNA and contribute to slowing down the evolution of cancer. While research on them is still ongoing to understand their overall impact on the body, they could be given alongside conventional treatments (radiotherapy and chemotherapy).

In oncology, the notion of “personalized medicine” or “precision medicine” (tailor-made treatments adapted to the person and specific to the type of cancer) is on everyone’s lips. Indeed, very general chemotherapies are not effective in all patients and also affect healthy tissues, causing many adverse effects. Choosing drugs based on the genetic and epigenetic characteristics of cancer offers the hope of seeing a better control of the disease appear and of sparing, to a certain extent, healthy tissue (with “targeted therapies”).

Thus, the methylome seems to have a bright future ahead of it. Even if punctuation does not appear, at first glance, essential to a sentence, it is essential for reading a text and for its proper understanding. We now know that cancer is a genetic and epigenetic disease and that commas count as much as consonants and vowels.

The methylome, a new (epi)genetic identity card for cancers