Investigating the DGR8 Syndrome


Nogué i Ansón, Clara 


Rare cancers are usually classified as rare diseases (those that affect less than 5 people in every 10,000 in the EU) that, due to the low incidence and the cost and complexity of research, are poorly studied. Despite the fact that cancer is usually sporadic, about 10% of cases have a hereditary component that explains the existence of hereditary cancer syndromes. These rare syndromes in the population explain about 5 to 10% of all cancers. Mainly, the rare syndromes have an autosomal dominant inheritance pattern and are caused by germline mutations that cause loss of function in tumor suppressor genes following the Kudson two-hit model. Specifically, this project focuses on syndromes caused by a germline mutation associated with the microRNA biogenesis pathway. The syndrome with germline mutations in DICER1, involved in the biogenesis of miRNAs. known as DICER1 syndrome, which includes a wide spectrum of benign tumors as well as rare, low-incidence cancers where the most common phenotype is familial multinodular goiter. Until this year, DICER1 was the only susceptibility gene for multinodular goiter. Recently a single germline pathogenic variant in the DGCR8 nuclear microprocessor (c.1552G> A; p.E518K) published by Rivera et al,. 2019, which, at the same time, is a hotspot in Wilms tumors, has been identified as an allele of susceptibility to the disease and it has been discovered that it is responsible for multinodular goiter together with peripheral schwannomatosis by studying its development in affected carriers in the three generations of a family. This fact highlighted the key role that microRNAs played in the development and maintenance of the thyroid gland.In the search to clarify the phenotype associated with germline variants of DGCR8, the study has been extended to new cases with susceptible disease phenotypes. Germline exome sequencing of three new cases has been carried out and we are currently collecting tumors. In Case 1, a heterozygous for the new variant (c.1552G> A; p.E518K) has been found that has developed thyroid nodules and thyroid cancer, such as those with DICER1 germline alterations in addition to multiple peripheral schwannomas. Due to the identification of this case, we have confirmed the association of this variant with the development of familial multinodular goiter and schwannomatosis in an unrelated patient. This fact opens new unknowns in relation to the pathogenic variants to DGCR8 and the multiple phenotypes associated with it or, if there are phenotypes not associated with cancer.
The second objective of the project involves the characterization of DGCR8- c.1552G> A; p.E518K mutant at the protein interaction level. To do this, we have analyzed the data of a proteomic characterization of the network of interactions of the DGCR8 wild type protein and the DGCR8-p.E518K protein. 94 interactors close to wt and mutant DGCR8 were analyzed and it has been identified which pathways, functions and tissues were involved to finally obtain the first four candidates (EIF6, EEF1A2, SMARCA1 and YTHDF3) that will first be validated in the laboratory.



Rivera Polo, Bárbara
Leivar Rico, Pablo 


IQS SE -  Undergraduate Program in Biotechnology