CNIO will help to improve cancer prevention and personalized diagnosis with the most powerful ‘gene reader’

The most advanced DNA reading machine on the market, a sequencer capable of reading tens of thousands of genomes a year, is now available to cancer researchers at the National Cancer Research Centre (CNIO). It is the most sophisticated tool currently available to analyse genetic material, the key capacity that will allow personalised medicine to really take off.

It is a NovaSeq-X Plus sequencer manufactured by the US company Illumina. It can sequence 20,000 genomes a year. Thanks to it, CNIO groups will accelerate the search for genes that increase cancer risk, and for markers that allow for early detection and determination of the best therapy in each case. They will also investigate the genetic evolution of a tumour on a single cell basis, which is important when trying to counteract metastasis and drug resistance.

“CNIO’s scientific strategy is directed toward the analysis of large amounts of genomic data and toward Artificial Intelligence, with the incorporation of groups working in these areas and with machines like this, capable of sequencing tens of thousands of genomes a year, at a cost that would have been unthinkable until very recently,” says Maria A. Blasco, CNIO’s scientific director. “CNIO will make a major contribution to achieving a much more personalised approach to medicine”.

As Fernando Peláez, director of CNIO’s Biotechnology Programme, explains, “what makes this equipment unique is that it allows more genomes to be read in less time, and it is substantially cheaper because the more the readings, the more the cost is diluted. It’s really impressive.”

What makes us unique beings

Sequencing is equivalent to reading the DNA, contained in the nucleus of each cell, forming the chromosomes. In DNA, the molecule from which genes are made, are the instructions for building the body, encoded in ‘biological language’. DNA has four chemical components, expressed with the letters A, T, C, G. In the human genome there are 3,000 million pairs of those four letters, which with their different combinations make up around 20,000 genes.

By following the instructions encoded in those genes, cells generate the thousands of different proteins that comprise the human body. There are countless variations in these instructions, and that is what guarantees individuality, from our unique face to aspects of our personality and the predisposition to develop certain diseases or to have side effects when taking different medications. Furthermore, errors in genes can lead to diseases, including cancer.

From 100 million per genome to less than 1,000

It is, therefore, important to know the multiple variants of the human genome in maximum detail. It is an area in which progress has been making great strides 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 gone down. In the early 2000s, sequencing a genome cost 100 million; a decade later it was around $10,000. With the NovaSeq-X Plus it can be reduced to a few hundred euros.

“It is a tool that will boost the research of many groups at CNIO,” explains Peláez. “It is instrumental for the Human Cancer Genetics Programme, but also for clinical research, where sequencing can guide therapeutic decisions. And of course for the most basic research, to understand the origin of diseases.”

Bringing genomic information to clinical practice

Orlando Domínguez, head of the Genomics Unit, and Anna González Neira, head of the Human Genotyping Unit-CEGEN, will coordinate access to the new sequencer.

“We will bring into clinical practice knowledge about genes that increase susceptibility to diseases like cancer or those that predict response to treatments. We will obtain information for personalising cancer screening programmes, and enhancing early detection and prevention,” says González Neira.

“We will also understand tumours better: we will sequence their entire genomes and we will identify somatic [non-inherited] mutations or alterations much more quickly and at a much lower cost,” she adds. “And we will contribute to the diagnosis of rare diseases, caused by genetic variants present in very few people.”

Open to the scientific community

The new sequencer is available to the whole scientific community through agreements with CNIO as a service offered by the Human Genotyping Unit-CEGEN.

SOME OF THE PROJECTS THAT USE THE NEW SEQUENCER:

Looking for pre-malignant lesions cell-by-cell

Geoff Macintyre, head of the CNIO Computational Oncology Group, studies so-called ‘complex and unstable genome tumours’, such as lung, brain, pancreas, prostate, ovaries or oesophagus.

These tumours are made up of cell populations that have undergone different genetic changes, so not all of them respond to treatment in the same way. That is why it is necessary to determine the changes in the genome of each tumour cell, and to do this the group uses the technique of ‘single cell genome sequencing’. The new sequencer allows us to analyse thousands of cells at once.

“In traditional sequencing, we combine and sequence the DNA of millions of cells, and we get an average reading,” explains Macintyre. “Single cell sequencing reveals the differences in each cell, which is important in determining the strategy of an anti-tumour treatment.”

Macintyre specifically investigates patterns that indicate chromosomal instability, a type of structural lesion in the genome that can cause cells to evolve into a malignant tumour. Detecting chromosomal instability in the cells would allow premalignant lesions to be found, which would pave the way to treating the tumour even before it appears: “It’s a step towards cancer prevention, my group’s long-term goal. We are just beginning, and it will take years, but the new sequencer will be a big boost.”

Including personal genetic risk in breast cancer screening programmes

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

However, this inherited genetic information is not yet taken into account in screening programmes, currently based on age and family history. González Neira’s research seeks to “personalise screening much more, by integrating genetic information to improve detection rates” she explains.

“The personalisation of screening would allow screening intervals to be individualised, and women at high risk could be offered preventive interventions,” she adds. “This will not only improve the effectiveness of screening, it will also optimise resources by channelling them to those who would benefit most from preventive interventions.”

Looking for genetic errors that cause cancer and rare diseases

CNIO is heavily involved in the Impact_VUSCan project, which analyses millions of genetic variants to identify those that most influence cancer predisposition. IMPaCT_VUSCan is part of the initiative for personalised medicine run by the Carlos III Health Institute (ISCIII).

The new sequencer is key to looking for new genes involved in cancer. It facilitates, for example, the analysis of the whole genome. As Mercedes Robledo, head of the CNIO Hereditary Endocrine Cancer Group, explains , “previously only the coding regions of the genome [those that translate into proteins] were sequenced, but we have seen that there are mutations in non-coding regions [previously considered ‘junk DNA’ because their function was unknown] that also affect the protein. It also allows us to look at chromosomal translocations, which cause alterations that can be pathological and are very difficult to detect. Now we can study them in whole families.”

“This will be of help not only for cancer but also for rare diseases, which are usually paediatric diseases,” she adds. Robledo’s group is investigating the rare tumour known as pheochromocytoma, and in recent decades has identified five of the twenty-two genes related to this disease.

About CNIO- ‘Friends of CNIO’

The National Cancer Research Centre (CNIO) is a public research institution. We are among the best cancer research centres in the world, both in scientific production and in developments that can lead to new therapies. Our goal is to improve cancer prevention, diagnosis and treatment. You can collaborate with cancer research through the Friends of CNIO, our philanthropic initiative aimed at private individuals and companies. 100% of all donations received go entirely to cancer research.

Imagen: @CireniaSketches / CNIO.