The biggest ever Spanish project to identify cancer risk genes kicks off

Currently, only some of those who are at higher risk than normal can know their predisposition to developing cancer. To help many more people know their risk and be able to prevent the onset of cancer, or detect it early, the IMPaCT_VUSCan project, has been launched, co-led by the Spanish National Cancer Research Center (CNIO) and the Bellvitge Biomedical Research Institute/Catalan Institute of Oncology (IDIBELL/ICO), and involving seven other Spanish research centers.

IMPaCT_VUSCan seeks to expand knowledge about the genetic variants that affect cancer predisposition [variants become different versions of a gene; there may be thousands of variants for each gene].

The first beneficiaries of this project will be families with high-risk genes that are passed down from parents to children, presenting therefore more cases of cancer than usual. IMPaCT_VUSCan will collect and analyse in-depth data from more than three hundred families with cases of familial cancer from all over Spain.

However, in the medium and long term, knowing more about the relationship between each genetic variant and cancer will bring personalised medicine closer to the entire population.

The project has received 3,179,990 euros in funding and will run until December 2025.

From familial cancer to personalized medicine for everyone

“We hope to improve the clinical management of family members with hereditary cancer,” says Mercedes Robledo, head of the Hereditary Endocrine Cancer Group at CNIO and principal investigator on the IMPaCT_VUSCan project. “This project will allow us over the coming years to identify which genetic variants, among the thousands carried by each individual, are related to the development of their cancer. That will further the development of personalized medicine for everyone.”

“Our approach is geared towards familial cancer, but the information we get through IMPaCT_VUSCan will also be useful in advancing our understanding of genes involved in cancer in general,” Robledo adds.

Dozens of genes that increase predisposition to cancer are already known

The predisposition to cancer is determined by both the mutations one is born with, and environmental factors such as lifestyle. Some people inherit from their parents mutations or variants in genes that increase the risk of developing the disease. As some of these variants are already known, today the Spanish National Health System can already detect and monitor those who carry them, to detect the disease early and personalise treatment.

This is done through familial cancer consultations, and it is a strategy that works. “Familial cancer consultations have already managed to halve the incidence of cancer in patients who are monitored these programs, and their life expectancy has increased by up to ten years,” says Conxi Lázaro, principal investigator of the project and head of the Hereditary Cancer Group at IDIBELL and the Catalan Institute of Oncology. “But many variants that influence the risk of developing cancer have yet to be identified”.

In breast cancer, for example, a dozen predisposing genes have already been identified, and two of them increase the risk of developing it by up to 70%. But these ten genes account for only half of the cases of hereditary breast cancer, meaning additional genetic factors related to susceptibility to this type of cancer have yet to be detected.

Uncertainty surrounding Variants of Unknown Significance (VUS)

Researchers know that most of the genetic variants they identify will be “of unknown significance”: “When we analyse the genomes from members of affected families, we find genetic variants for which no effect has been previously shown, and therefore we do not know if they are responsible for the development of the disease in that family,” Robledo explains.

These Variants of Unknown Significance (VUS) generate a lot of frustration: “In the end, what we want is for the information that reaches a doctor to be useful, helping them to decide if a variant is important or not. Precisely for this reason the IMPaCT_VUSCan project makes sense,” Robledo says.

“Many of the new variants observed do not usually have sufficient evidence to be considered pathogenic or benign, and are ultimately classified as VUS,” explain the researchers on the project. “A VUS can be confusing to patients and doctors because it creates uncertainty, and cannot be used to guide diagnosis or treatment.”

Artificial Intelligence to ‘solve’ VUS

The aim of IMPaCT_VUSCan is to move towards “solving VUS”, clarifying their role in the predisposition to cancer.

Given the large number of VUS that could foreseeably be identified in an individual’s genome, the first step will be to set priorities. That is the work of bioinformatics groups, which will analyse vast amounts of genomic information and develop Artificial Intelligence methods to identify the most important variants. Their predictions must be validated with functional tests.

As variants are resolved, they will be included in the genetic variant databases, which will ultimately serve to improve the accuracy and personalisation of cancer diagnoses and treatments.

In addition to CNIO and IDIBELL, IMPaCT_VUSCan involves a further seven research centers throughout Spain: Sant Pau Institute of Health Research (IIB Sant Pau); the Navarra Institute of Health Research (IdiSNA); the San Carlos Clinical Hospital Research Institute (IdISSC); the Galician Public Foundation for Genome Medicine (FPGMX); the Foundation for the Promotion of Health and Biomedical Research in the Region of Valencia (Fisabio); the Balearic Islands Institute of Health Research (IDISBA); the La Paz Institute of Health Research (IdiPaz).

About the IMPaCT Personalised Medicine Infrastructure (ISCIII)

Since 2020, ISCIII has been developing the IMPaCT Personalised Medicine Infrastructure, with three main pillars: Predictive Medicine, Genomic Medicine and Data Science, which, individually or as a whole within IMPaCT, are designed to serve the R&D/Innovation system with a focus on Precision Medicine.

IMPaCT-GENóMICA is a cooperative infrastructure divided into hubs to conduct highly complex genetic studies based on research technologies, one of which is IMPaCT_VUSCan, funded by ISCIII, within the annual calls for funding of projects associated with IMPaCT.

CNIO groups in IMPaCT_VUSCan

Mercedes Robledo, Head of the Hereditary Endocrine Cancer Group: identification of genetic factors involved in cancer susceptibility.
Sandra Rodríguez, head of the Molecular Cytogenetics and Genome Editing Unit. Using CRISPR genome editing technology, she creates models that recapitulate the chromosomal and genetic alterations of cancer.
Fátima al-Shahrour, head of the CNIO Bioinformatics Unit. She develops computations to analyse cancer genomes and prioritise pharmacological targets based on tumour alterations.
Óscar Llorca, head of the Macromolecular Complexes in response to DNA Damage group. He determines the 3D structure of relevant large macromolecular complexes in cancer
Maria Currás-Freixes, head of the Familial Cancer Clinical Unit.
Anna González-Neira, head of the Human Genotyping Unit – CEGEN – CNIO, who will also provide support in the analysis of samples.