Genetic roadmap leading from benign thyroid tumors to cancer described

A research group from IDIBELL-ICO, led by Dr. Bárbara Rivera, has managed to trace for the first time the molecular route that certain thyroid tumors follow to go from being benign nodules to malignant cancers. The team, which also included researchers from Institut de Recerca de Sant Joan de Déu (IRSJD), has focused the study on a specific type of tumor, 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 cancer progression. The discovery, recently published in the scientific journal JCI Insight, opens the door to locating new diagnostic and prognostic biomarkers and designing better surveillance strategies for patients, especially pediatric 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 moment they begin to form until they are functional. The DICER1 and DGCR8 genes are key pieces in this machinery and, therefore, when they are mutated, the susceptibility to developing tumors is greater. Specifically, patients with hereditary alterations in DICER1 are at risk of developing up to 30 different types of tumors, some with a very poor prognosis. For this reason, patients are subjected to very intense monitoring programs.

This greater predisposition to tumors linked to mutations in DICER1 or DGCR8 has been known for years, but until now the exact steps that lead from a benign lesion, caused by mutations in any of these genes, to cancer had not been 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 IDIBELL-ICO Hereditary Cancer research group.

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

Two routes to thyroid cancer

The study reveals that there are two main routes depending on the gene affected. In the first, the mutation in DICER1, by itself, may be enough to upset the balance of miRNAs and lead to thyroid cancer (although, in some more aggressive cases, secondary mutations in the TP53 gene appear as companions). In the second, the mutation in DGCR8 seems to promote an ideal scenario for a second mutation to be acquired, usually in genes of the MAPK pathway, to go from a benign to a malignant thyroid lesion.

"In either of the two routes, we have seen that as alterations accumulate in the balance of miRNAs produced by the cells, the tumor becomes more malignant", specifies Anne-Sophie Chong, doctoral student at IDIBELL and the UB, and first author of the study. At first, it seems that benign tumors try to compensate for the problems in manufacturing miRNAs 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.

In addition, in addition to describing cancer progression, the researchers have 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 take into account those tumors that present defects in the synthesis of miRNAs, a very frequent profile in pediatric oncology. This 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 tumors are benign or have already started the path to cancer, which represents an important step in the management of these high-risk patients," explains Dr. Rivera.

The translation of the discovery for patients

Beyond helping to better understand the biology of thyroid tumors and proposing new biomarkers, the research of Dr. Bárbara Rivera's team opens the door to rapid applications in the management of thyroid cancer, especially in families with a hereditary predisposition to cancer (such as those with inherited mutations in DICER1).

Having defined the steps of progression to thyroid cancer could allow, in the future, to better stratify the risk of these patients. Above all, closer surveillance could be guaranteed 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 research staff from Universitat de Barcelona, la McGill University (Canada), Insitut de Recerca Sant Joan de Déu (IRSJD), SJD Barcelona Children's Hospital (HSJD) and Centre Nacional d'Investigació Oncològica (CNIO), as well as the Pathology Departments of Hospital Universitari de Bellvitge, l'Hospital Ramón y Cajal i l'Hospital Universitari Arnau de Vilanova. It has also had the support of La Marató de 3Cat and Iberdrola through Asociación Española Contra el Cáncer (AECC).