Since human DNA was sequenced in 2001, the comprehensive genomic characterization of tumors – the knowledge of all the genes found in the specific cells of each tumor – has become one of the main objectives of cancer researchers. The Pan-Cancer Analysis of Whole Genomes consortium, which already succeeded in sequencing twelve types of cancer in 2013, has taken a decisive step with the publication in Nature of the atlas of the cancer genome . This is the most ambitious study to date on tumor DNA . More than 1,200 researchers from 37 countries have participated, sequencing the genome of 2,600 samples of 38 types of tumors. While previous research focused exclusively on the exome – the coding regions of proteins, a small part of tumor DNA – this analysis sequences the entire DNA of cancer cells, which will help to discover tumor mutations in almost all of them – 95% – of patients . In addition, the mapping remains open and many more types of tumors will be able to be sequenced over time.
For the director of the Oncohealth Institute of the Jiménez Díaz Foundation, Jesús García-Foncillas, one of the key findings of the new map is that there must be between two and five causal mutations – those that occur for a cause, such as tobacco or poor diet – in a specific cell for the tumor to appear. This implies that cancer does not emerge “as an isolated event, nor is it easy for it to set in motion.” There must be a series of alterations that accumulate until the disease occurs . This leads us to think “that the knowledge and detection of these alterations could play a fundamental role in the way of planning prevention,” says García-Foncillas.
Thus, carrying out an early study as soon as some of these alterations occur could allow anticipating cancer. For García-Foncillas, this is an “exciting promise” for cancer research, especially with regard to prevention and to undertake a different “and more rational approach to early diagnosis”. It is conceivable that, although there are targeted drugs, better knowledge of the biology of the tumor, specifically, the most important mutations that characterize it, makes the therapeutic objective focus on these and not on others, in order to sharpen the aim of the tumor. cancer treatment.
Interview with Nuria López-Bigas: “Now we can know which mutations cause cancer”
The laboratory directed by biologist Nuria López-Bigas at the Institute for Biomedical Research (IRB) in Barcelona focuses its work on the identification of mutations that cause tumor development . These have been key to giving birth to the Pan-Cancer project.
What has been the contribution of your institute to the Pan-Cancer project?
We have done the analysis of cancer-causing mutations and we have also participated in another project to identify the mutational processes that are observed in the tumor, that is, to see if the mutations are caused by tobacco, by ultraviolet light or by certain internal processes of the cell . Where we have made a more direct contribution is in the analysis of tumor-causing mutations. Most of these have no implication in tumor development; in fact, we can only say of a few that they are responsible for the disease. Using bioinformatic algorithms we are able to establish which of these mutations turn out to be the ones that trigger cancer.
So can we say that the mutations causing the tumor are known?
We have been able to note and identify the mutations causing them in each of the 2,600 tumors studied; between two and five. In almost all genomes we have found some. This means that mutations are necessary for tumor development, although they are probably not enough by themselves . There may be cells in the body that have certain mutations, but for context or other reasons they do not turn cancerous. But they are necessary, because all tumors have these types of alterations.
What applications can the knowledge of all this data have?
We now better understand the molecular causes of cancer and what the genome of tumor cells is like, which can be applied in personalized medicine for the disease . In some cases it is already being used in clinical practice. Now it is necessary to better understand the characteristics of the cancer genome in order to apply it more. The paradigm is that all tumors are different, which suggests that they will require different treatments. Sequencing the genome of the patient’s cancer cells shows whether or not there are certain mutations and, based on this, it is decided whether one treatment or another is more appropriate.
What steps will have to be taken next?
Ideally, part of these studies should be carried out in the clinical context, because it would be much more linked to the patients, the decisions and the clinical information of these tumors. In Spain we are a little behind, but in places like the United Kingdom and the Netherlands it is already being implemented in clinical practice.
This is how the atlas is drawn
In 2013, scientists from the Cancer Genome Atlas (TCGA) project collected samples of these twelve tumor types : glioblastoma multiforme, breast carcinoma, lung adenocarcinoma, bladder carcinoma, cervical uterine and endometrial carcinoma, acute lymphoblastic myeloid leukemia, squamous cell carcinomas. neck and head, squamous cell carcinoma of the lung, ovarian carcinoma, renal cell carcinoma, colon adenocarcinoma and rectal adenocarcinoma.
They then analyzed mutations, copy number of genomic sequences, gene expression, DNA methylation, and other alterations in the development of each cancer. This information went to the TCGA data coordination center where, with the help of other researchers and centers, common biological pathways and the activation or inhibition of certain regulatory elements of these pathways were detected. The data was then deposited in the Synapse database at the disposal of cancer research. Today this work is ongoing and the genome of 2,600 samples from 38 classes of tumors has already been sequenced.
