New gene involved in familial breast cancer discovered

A study led by UAB and Hospital de Sant Pau researcher Jordi Durallé deminstrates with massive sequencing techniques that the frequency of carriers of EDC4 mutations in patients with familial cancer is six times greater than in healthy individuals.

14/03/2018

An international consortium of researchers led by Dr Jordi Surrallés, director of the Genetics Service at the Hospital de Sant Pau, professor of Genetics at the UAB and researcher at the Centre for Biomedical Network Research on Rare Diseases (CIBERER), and by Dr Miquel Àngel Pujana, director of the ProCURE Research Programme of the Catalan Institute of Oncology (ICO, IDIBELL), has identified the gene implied in this type of cancer, known as EDC4.

Researchers have demonstrated that the gene encodes a protein which interacts with BRCA1 and plays an essential role in DNA repair through the homologous recombination mechanism. By using massive sequencing techniques with more than one thousand breast cancer patients and healthy control patients, researchers observed that the frequency of carriers of EDC4 mutations in patients with familial cancer is six times greater than in healthy individuals. Moreover, researchers analysed in detail the effect of these mutations by using advanced engineering and genetic edition techniques and were able to demonstrate that the mutations are pathogenic since they destroy the repair capacities of the EDC4 gene. Finally, the authors also demonstrated that cells with mutated EDC4 are highly sensitive to PARP inhibitors, and this presents an opportunity to explore possible therapeutic options for patients with these gene mutations.

Genetic Origin of Breast Cancer

Breast cancer is one of the most prevalent cancers in our society. It is calculated that some 5-10% of these types of cancers are hereditary, often appearing in several members of a family at relatively young ages. The most important genes involved are the BRCA1 and BRCA2 genes, discovered in the mid-1990s. BRCA1 is a tumour suppressor gene involved in DNA repair through homologous recombination and in preserving the integrity of the genome. Breast and ovarian tumours lacking one of these two genes are more sensitive to a new-generation chemotherapy, the PARP inhibitors, which is revolutionising drug treatments in this type of cancer. The discovery of new genes involved in these repair mechanisms is very important in order to understand the development of these tumours and delve more deeply into their therapeutic vulnerabilities.

Hereditary Cancer at Hospital de Sant Pau

Hospital de Sant Pau is a pioneering centre in Spain in the study of BRCA1 and BRCA2 genes in patients with hereditary breast and ovarian cancer. It was also the first hospital in Spain to include genetic analyses of these genes with the aim of offering better assistance to patients and their families. Dr Teresa Ramón y Cajal coordinates the Genetic Advisory Unit of the Medical Oncology Service, directed by Dr Agustí Barnadas. Dr Adriana Lasa coordinates the Oncogenetic Unit of the hospital's Genetic Service, directed by Dr Jordi Surrallés. Both hospital units work jointly since 1995 to offer diagnosis and assessment services in familial and hereditary cancer, as well as clinical monitoring, prevention, early detection and highly specialised treatments for patients. The experience they have acquired throughout the years with thousands of families have allowed them to launch several translational biomedical research projects which have benefited numerous patients. Hospital de Sant Pau has gradually incorporated the latest technologies in genetic diagnostics. It currently analyses a panel of multiple genes with a predisposition for tumours thanks to new-generation massive sequencing techniques. The impulse of genomic medicine at the hospital has been possible thanks to the incorporation of new massive sequencers at the Area of Clinical Genomics and the addition of new massive sequencing medical staff, including new technicians and a new practitioner specialised in bioinformatics. These improvements contribute to making Hospital de Sant Pau one of the healthcare centres in Spain with the greatest capacity for sequencing, precision diagnostics and personalised therapeutic treatments.

Hereditary Cancer at the ICO

As a public service, the mission of the ICO's Hereditary Cancer Programme is to work to reduce the impact of cancer in Catalonia through the identification of individuals and families with an increased risk of developing cancer, due to being carriers of mutations in highly penetrant cancer predisposition genes. Its range reaches over 50% of the adult population of Catalonia and includes the Genetic Advisory Unit of the ICO centres located in L'Hospitalet, Badalona and Girona. The programme conducts more than 2,000 genetic studies annually to determine mutations in the BRCA1/2 genes and in other genes known to be related to breast cancer.

Original article:

Gonzalo Hernández, Maria José Ramírez, Jordi Minguillón, Paco Quiles, Gorka Ruiz de Garibay, Miriam Aza-Carmona, Massimo Bogliolo, Roser Pujol, Rosario Prados-Carvajal, Juana Fernández, Nadia García, Adrià López, Sara Gutiérrez-Enríquez, Orland Diez, Javier Benítez, Mónica Salinas, Alex Teulé, Joan Brunet, Paolo Radice, Paolo Peterlongo, Detlev Schindler, Pablo Huertas, Xosé S Puente, Conxi Lázaro, Miquel Àngel Pujana and Jordi Surrallés (2018) "Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1." Nature Communications (2018) 9:967.