After completing the human genome sequencing project in 2001, researchers focussed on identifying all of the genes central to tumour formation. The Pan-Cancer Analysis of Whole Genomes consortium, which had sequenced 12 different cancers in 2013, has recently published a cancer genome atlas in the scientific journal Nature.
More than 1200 scientists from 37 nations helped sequence the genome—all of the genes in 2,600 samples encompassing 38 tumour variants. In the past, researchers had sequenced only the protein-encoding areas of the genome, this newer analysis takes into account all of the DNA in cancer cells, uncovering numerous tumour mutations that represent 95 per cent of patients. Moreover, mapping these cancer genomes is an ongoing process as new sequences from different tumours will continue to be added to the atlas.
Two to five causal mutations direct tumour formation, according to the director of the Oncohealth Institute of the Jiménez Díaz Foundation, Jesús García-Foncillas.. For this to happen it appears that cancer is rarely “a single event, nor is it easy to set it in motion.” So, several mutations would need to occur for cancer to develop. “The knowledge and detection of these alterations could play a fundamental role in the way we approach prevention,” says García-Foncillas. Anticipating cancer would be easier if an early test were carried out soon after these cancer-causing changes had taken place. García-Foncillas considers this an “exciting promise” for cancer research, especially prevention of the disease with a “more rational approach to early diagnosis.” While targeted drugs exist, a more well-rounded understanding of the tumour biology will help pinpoint crucial genetic mutations, and aid in sharpening the therapeutic focus on those, eventually improving cancer treatment.
Here is how the atlas was made
In 2013, researchers from The Cancer Genome Atlas (TCGA) project procured samples of 12 tumour types—glioblastoma multiforme, breast carcinoma, lung adenocarcinoma, bladder carcinoma, cervical and endometrial carcinoma, acute lymphoblastic myeloid leukaemia, squamous cell carcinomas of the neck and head, squamous cell carcinoma of the lung, ovarian carcinoma, renal cell carcinoma, colon adenocarcinoma and rectal adenocarcinoma.
For each cancer type, the team analysed the genome, including any mutations, the numbers of genomic sequence copies, gene expression, DNA methylation, and developmental irregularities. At the TCGA data coordination centre, the different research organizations that were involved identified common biological and regulatory pathways that were evidently responsible. These data were collated at the Synapse database.
Interview with Nuria López-Bigas: “Now, we can know which mutations cause cancer.”
Biologist Nuria López-Bigas' laboratory at the Institute of Biomedical Research in Barcelona primarily works on the identification of tumour-causing mutations. Their project was chiefly involved in the development of the Pan-Cancer project.
What has been the contribution of your institute to the Pan-Cancer project?
We have analysed the mutations that cause cancer and have also participated in another project to identify the mutational processes observed in the tumour, that is, to see whether the mutations are caused by tobacco, by ultraviolet light or by certain internal processes in the cell. Where we have made a more direct contribution is in the analysis of the mutations causing the tumour. Most of these have no involvement in the development of the tumour; 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 the cancer.
So can we say that the tumour-causing mutations are known?
We have been able to annotate and identify in each of the 2,600 tumours studied which are the mutations causing them; between two and five. In almost all genomes we have found one. This means that mutations are necessary for tumour development, although surely alone they are not enough. There may be cells in the body that have certain mutations, but for context or other reasons they do not become cancerous. But they are necessary because all tumours have this type of alteration.
What applications can have the knowledge of all this data?
We now better understand the molecular causes of cancer and what the tumour cell genome looks like, which can be applied in personalized medicine of the disease. In some cases, it is already being used in clinical practice. Now we must better understand the characteristics of the cancer genome in order to apply it more. The paradigm is that all tumours are different, which suggests that they will require different treatments. By sequencing the genome of the patient's cancer cells, it is seen whether or not there are certain mutations and, based on this, it is decided whether one treatment or the other is more appropriate.
What steps will have to be taken later?
Ideally, part of these studies should be done in the clinical context, because it would be much more linked to the patients, decisions and clinical information of these tumours. 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.