Although cancer always has a genetic origin, only 5% to 10% of cases are hereditary. In these cases, what is transmitted from parents to children is not the cancer itself, but a predisposition to develop it. This predisposition often manifests itself with diagnoses at young ages, multiple primary tumors in the same patient, aggregation of cases within the same family, or rare tumors.
In situations like this, it is vital to identify the cause of hereditary predisposition to cancer in order to articulate prevention programs, early detection and, sometimes, precision cancer treatment for affected families. That way, the members of the carrier family can be closely monitored in anticipation of the probable appearance of the types of tumors associated with the corresponding genetic alteration. However, current genetic tests allow the hereditary cause of cancer to be identified in only approximately 11% of families with clinical suspicion. This leaves almost 90% of people without a clear explanation, and forces medical follow-up to be based solely on personal and family history.
In this context, two independent but complementary studies led by Dr. Laura Valle and Dr. Conxi Lázaro, respectively, principal investigators of the ICO-IDIBELL Hereditary Cancer Program – in which members of various European institutions have also participated in the former, and the ICO Bioinformatics for Precision Oncology Unit in the latter – have allowed the identification of mutations that until now had gone undetected in routine genetic diagnosis.
Providing answers to reduce uncertainty: the success of the complete genomic study
The first major milestone has been reached within the European Solve-RD project, focused on solving undiagnosed cases of rare diseases. The project, funded by the European Commission, is made up of six European reference networks in different rare diseases, including ERN GENTURIS, dedicated to hereditary cancer, and of which the Hereditary Cancer research group of IDIBELL-ICO is a part. Participation in this European consortium aligns perfectly with REMMA Bellvitge, Bellvitge’s research program in rare adult diseases, such as hereditary cancer syndromes, which seeks to ensure innovative solutions and answers for patients who are often underserved.
The IDIBELL-ICO team led by Dr. Laura Valle, together with Dr. Carla Oliveira from the i3S-IPATIMUP in Portugal, has led the project by reanalyzing the cases of 98 patients without a genetic diagnosis but with a very clear suspicion of hereditary cancer. Most patients were young adults (mean age 23 years), with multiple primary cancers in various organs, or with gastrointestinal polyposis at an early age. In all of them, whole genome sequencing was carried out to try to identify genetic variants that had not been detected before, either because they were found in regions of the genome that had not been studied, or because they were present only in some tissues and, to a lesser extent, in blood cells, and had escaped the initial genetic test.
The results of the study, published in JCO Precision Oncology, show that, thanks to the reanalysis of patient data, diagnosis has increased by 6%. “Increasing diagnostic yield has a very relevant impact, especially for patients and families who finally receive a conclusive genetic diagnosis. Each new genetic diagnosis allows us to offer personalized clinical management, based on the specific risks associated with each gene. This translates into prevention measures, early detection and more precise treatments, as well as facilitating the genetic study of patients’ relatives,” explains Dr. Valle, also researcher at CIBERONC. “Providing answers is key to reduce uncertainty and improve the clinical management of carriers; it is life-giving, and it is invaluable.”
GRIDSS: proprietary technology to reveal hidden mutations
Complementing this study, the Hereditary Cancer group at IDIBELL-ICO continues to work to improve the diagnostic strategy for unresolved cases of hereditary cancer. One way to do this is by optimizing current bioinformatics tools, as has been the case of a second study led by Dr. Conxi Lázaro and published in the European Journal of Human Genetics.
Dr. Lázaro’s group has analyzed nearly 10,000 people with suspected hereditary cancer, focusing specifically on a type of DNA alterations – intermediate-sized structural variants – that often go unnoticed despite playing a key role in the development of tumors. Adapting the GRIDSS bioinformatics tool, they have developed their own strategy to solve the diagnosis of eight families with a predisposition to breast, ovarian, colon and prostate tumours. “We have done so by taking advantage of the same sequencing data that are already generated in clinical diagnosis,” explain Elisabet Munté and Paula Rofes, first authors of the study. “This means that we do not have to do new tests systematically, but that it is enough to analyze, in another way, the information we already have.”
In addition, the methodology developed is easily applicable to other laboratories and does not require major changes in clinical practice, which could contribute to more precise, preventive and accessible medicine.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus d’Excelencia Internacional of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).