Thyroid cancer and double-strand DNA break repair: The potential role of the MRN complex pathogenic variants

The molecular drivers of thyroid cancer are predominantly involved in the MAP kinase pathway, especially the BRAF and RAS pathogenic variants. The DNA repair pathways are rarely implicated in thyroid tumorigenesis. The MRE11-RAD50-NBS1 (MRN) complex is a key mediator of homologous recombination mode of double-strand break repair, and its role in thyroid cancer is poorly understood. We describe a patient with radioactive iodine-refractory, metastatic oncocytic thyroid carcinoma with an NBN gene (c.2166_2167delGCinsAT) pathogenic variant, who developed progressive disease despite receiving systemic therapy with lenvatinib and pembrolizumab. A gene query analysis for the three MRN complex genes (MRE11, RAD50, and NBN) across three thyroid cancer repositories on the cBioPortal database showed a prevalence of pathogenic variants in one or more MRN complex genes in 35/762 (4.6%) patients, and all the 35 patients had anaplastic thyroid cancer (ATC). Upon filtering the dataset to include only ATCs, the pathogenic variant prevalence increased to 22.2% (35/158 patients). The overall survival in ATC patients with MRN complex gene alterations was similar to ATC patients without the altered MRN complex genes [HR: 1.42 (95% CI: 0.93-2.17)]. A mutual exclusivity analysis demonstrated a tendency for pathogenic variants in one MRN complex genes to co-occur with pathogenic variants in the other two MRN complex genes. In conclusion, the MRN complex pathogenic variants could be potentially oncogenic in TCs and may be linked to aggressive forms of TC.