A research group from IDIBELL-ICO, led by Dr. Bárbara Rivera, has managed to trace for the first time the molecular route followed by certain thyroid tumours to evolve from benign nodules to malignant cancers. The team has focused on the study of an specific type of tumour, more prevalent among children, characterized by mutations in two genes that process small regulatory molecules called microRNAs (miRNAs).

Thanks to state-of-the-art multiomic techniques, the researchers have been able to identify the genetic and epigenetic changes that dictate cancerous progression. The discovery, recently published in the scientific journal JCI Insight, opens the door to locate new biomarkers for diagnosis and prognosis and to design better surveillance strategies for patients, especially paediatric patients.

A linear and progressive accumulation of errors

MicroRNAs are small molecules that strictly regulate gene expression and play a fundamental role in many biological processes, including cancer. Being so important, their biogenesis process is very well orchestrated, from the first steps until they are fully functional. DICER1 and DGCR8 genes are key pieces in this machinery and, therefore, when they are mutated, the susceptibility to developing tumours is greater. Specifically, patients with hereditary alterations in DICER1 are at risk of developing up to 30 different types of tumours, some of which have very poor prognosis. In those cases, patients are subjected to very intensive monitoring programs.

For years, this greater predisposition to tumours linked to mutations in DICER1 or DGCR8 has been known, but until now the exact steps that lead from a benign injury, caused by mutations in any of these genes, to cancer had not been yet described. “We did not know why some benign lesions derived from mutations in DICER1 or DGCR8 remained benign, and others became malignant,” explains Dr. Bárbara Rivera, principal investigator of the Hereditary cancer research group at IDIBELL-ICO.

Now, thanks to the characterization of the molecular landscape found in benign and malignant lesions of patient samples, the IDIBELL team has been able to reconstruct the history of genetic events that occur until the malignant transformation. “We have been able to describe a progressive, specific and linear accumulation of genetic alterations that guide us from the initial benign injury to thyroid cancer,” adds Dr. Rivera.

Two routes to thyroid cancer

The study reveals that there are two main routes according to the affected gene. In the first, the mutation in DICER1, by itself, may be sufficient to misbalance the miRNAs and lead to thyroid cancer (although, in some cases more aggressive secondary mutations appear in the TP53 gene). In the second, the mutation in DGCR8 seems to promote an ideal scenario for the acquisition of a second mutation, usually in genes of the MAPK pathway, to move from a benign to a malignant thyroid injury.

“In either of the two routes, we have seen that as alterations accumulate in the balance of miRNAs produced by cells, the tumor becomes more malignant”, specifies Anne-Sophie Chong, PhD student at IDIBELL and the UB, first author of the study. At first, it seems that benign tumours try to compensate for the problems of the miRNA-making process by activating more genes that encode them, “but this compensatory rescue mechanism ends up failing, and the production of miRNAs is greatly affected,” she concludes.

Besides describing cancerous progression, researchers have also identified the loss of a series of miRNAs as predictors of malignancy. This finding is fundamental for clinical practice, since current biomarker tests for thyroid cancer do not usually consider those tumors that present defects in miRNA synthesis, a very common profile in pediatric oncology. It still needs to be corroborated, but the results are promising: “This small group of miRNAs could represent the key biomarker to differentiate whether these thyroid tumours are benign or have already started the path to cancer, which represents an important step in the management of these high-risk patients,” says Dr. Rivera.

The translation of the discovery by patients

Beyond helping to better understand the biology of thyroid tumours and to propose new biomarkers, the research carried out by Dr Bárbara Rivera opens the door to rapid applications in the management of thyroid cancer, especially in families with hereditary predisposition to cancer (such as those with inherited mutations in DICER1).

Having defined the steps of progression towards thyroid cancer could, in the future, allow the better risk stratification of these patients. Above all, closer surveillance could be ensured for those who present risk mutations, acting before the disease progresses to more aggressive forms and offering more precise genetic advice.

This research has had the collaboration of the research staff of the University of Barcelona, McGill University (Canada), the Sant Joan de Déu Barcelona Children’s Hospital, the Sant Joan de Déu Research Institute, and the National Cancer Research Center (CNIO), as well as the Pathology Departments of the Bellvitge University Hospital, the Ramón y Cajal Hospital and the Arnau de Vilanova University Hospital. In addition, it has had the support of La Marató de 3Cat and Iberdrola through the Asociación Española Contra el Cáncer (AECC).

About Bellvitge’s Comprehensive Cancer Center (CCC)

This research is part of the Bellvitge Health Campus’s work as a Comprehensive Cancer Center (CCC), the highest European recognition in the field of oncology, awarded by the Organization of European Cancer Institutes (OECI). It is the only CCC in Spain and Catalonia, involving four independent public institutions (Bellvitge Hospital, IDIBELL, ICO, and UB), that takes a coordinated, networked approach to cancer with a team of over 1,500 professionals who lead efforts from research and prevention to comprehensive care.

About IDIBELL

The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, 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 of International Excellence 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 centers 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 Center of the AECC Scientific Foundation (FCAECC).