Most powerful ‘gene reading machine’ for better cancer treatment

It is the most sophisticated genetic analysis tool available today and holds key potential for the development of personalized medicine. This is the NovaSeq-X Plus sequencing device from the American company Illumina, capable of sequencing more than 20,000 genomes per year. With its help, CNIO groups will accelerate search for cancer susceptibility genes, and markers that allow it to be discovered early and determine the best therapy in each case. They will also investigate genetic evolution of tumor cell by cell, something important for combating treatment resistance.

“The CNIO’s scientific strategy aims to analyze large volumes of genomic data and artificial intelligence, with teams that work in these areas and with machines like this capable of sequencing tens of thousands of genomes per year at low cost. just recently this would have been unthinkable,” he says. Maria A. Blasco, scientific director of the Central Scientific Research Institute. “At CNIO we will make significant contributions to much more personalized medicine.”

How does this explain Fernando Pelaez, director of the CNIO Biotechnology Program, “What makes this equipment unique is that it allows you to read more genomes in less time, and it is significantly cheaper because the more reads, the more the cost goes down. It’s really impressive.”

What makes us unique creatures

Sequencing is equivalent to reading the DNA that is found in the nucleus of every cell and forms chromosomes. DNA, the molecule that makes up genes, contains instructions for building the body, encoded in biological language. DNA is made up of four chemical parts, labeled A, T, C, G; There are 3,000 million pairs of these four letters in the human genome, which in various combinations make up about 20,000 genes.

By following the instructions encoded in these genes, cells produce thousands of different proteins that make up the human body. The options in these instructions are countless, and this is what guarantees individuality: face, aspects of personality, predisposition to developing diseases or to this or that drug that causes side effects, etc. If there are errors in the genes, diseases may appear, including including cancer.

From 100 million per genome to less than 1000

For all of the above, it is important to know as much as possible about the numerous variants of the human genome. This is an area in which progress has been made at a rapid pace since the turn of the century.

To sequence the human genome for the first time in 2003, hundreds of groups around the world collaborated for more than a decade. Since then, sequencing techniques have advanced as much as costs have decreased. In the early 2000s, genome sequencing cost 100 million; Ten years later it was around 10,000 euros. With NovaSeq-X Plus this amount can be reduced to several hundred euros.

“This team will contribute to the research of many CNIO groups,” explains Pelaez. “This is useful for human cancer genetics programs and clinical trials, where sequencing can guide therapeutic decisions. And, of course, in the most fundamental research, to understand the origin of diseases.”

Bring genomic information to the clinic

Anna Gonzalez NeiraHead of the Human Genotyping Unit at CEGEN and Orlando Dominguez, head of genomics, will coordinate access to the new sequencer. “We will bring into clinical practice knowledge about susceptibility genes for diseases such as cancer or those that predict response to treatment. We will gain information to personalize cancer screening programs and improve early detection and prevention,” says González Neira.

Also, “we will know tumors better: we will sequence their entire genomes and identify mutations or somatic changes (not inherited) much faster and cheaper,” he adds. “And we will facilitate the diagnosis of rare diseases caused by genetic variants present in a very small number of people.”

The new sequencing equipment is available to the entire scientific community through the CEGEN Human Genotyping Unit.

Projects with a new sequencer: precancerous lesions

Jeff McIntyreHead of the Computational Oncology Group at the CNIO, studies so-called “tumors with complex and unstable genomes”, such as tumors of the lung, brain, pancreas, prostate, ovary or esophagus.

These tumors are made up of populations of cells that have undergone different genetic changes, so not all of them respond equally to treatment. This is why it is necessary to identify changes in the genome of each tumor cell, and to do this the team uses the technique of “single-cell genome sequencing”. The sequencer allows you to analyze the genome of thousands of cells simultaneously.

“With traditional sequencing, you pool and sequence DNA from millions of cells and get an average,” explains McIntyre. “Single-cell sequencing reveals differences in each cell, which is important for determining anticancer treatment strategies.”

McIntyre is investigating patterns that indicate chromosomal instability, a type of structural damage to the genome that can cause cells to develop into cancer. Detecting chromosomal instability in cells would allow us to detect precancerous lesions, which would open up the possibility of treating tumors before they appear: “This is a long-term goal of my group. “We’re just getting started and it will take years, but the new sequencer will be a big boost.”

Incorporate personal genetic risk into breast cancer screening programs.

In breast cancer, several genes have been identified that are associated with an increased risk of its development. In addition to BRCA1 and BRCA2, discovered in the late 1990s, in recent years it has been discovered that the combination of several genetic variants, together with environmental factors, can have a cumulative effect and influence risk.

However, this inherited genetic information is still not taken into account in screening programs based today on age and family history. González Neira’s research aims to “make screening more personalized by integrating genetic information to improve detection rates,” he explains.

“Personalizing screening will allow us to individualize screening intervals and offer preventative interventions to high-risk women,” he adds. “This will not only improve screening efficiency, but will also optimize resources, directing them to those who would benefit most from preventative measures.”

Finding genetic errors that cause cancer and rare diseases

CNIO is actively involved in IMPaCT_VUSCan, a project that analyzes millions of genetic variants to identify those that most influence cancer susceptibility. IMPaCT_VUSCan is part of the Personalized Medicine Initiative of the Carlos III Health Institute (ISCiii).

A new sequencer holds the key to finding genes involved in cancer development. This makes it easier, for example, to analyze the entire genome.

How does this explain Mercedes Robledo, head of the CNIO Hereditary Endocrine Cancer Group, “previously only the coding regions of the genome (those that are translated into proteins) were sequenced, but it is now known that mutations exist in the non-coding regions (previously considered ‘junk DNA’). ‘), which affect protein. It also allows us to observe chromosomal translocations, which are very difficult to detect and can cause changes. Now we can study them with whole families.”

“This will be useful not only for cancer, but also for rare diseases, which are usually pediatric diseases,” he adds. Robledo’s group is investigating the rare tumor pheochromocytoma and has identified five of the twenty-two genes associated with the disease.

Fountain: TsNIO