Germinal DICER1 Mutations in multinodular Goiter during Childhood and risk for Differentiated thyroid Carcinoma

  • Background/purpose: DICER1 is a member of the Ribonuclease III family that plays a crucial role in the biogenesis and the maturation of microRNAs. Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with variable penetrance, the highest of which is that of thyroid pathologies.We will evaluate the association of differentiated thyroid cancer with or without MNG in patients diagnosed as Dicer 1-syndrome.

    Methods: We report a series of 11 families whose diagnosis for DICER1-syndrome was done for most of them on MNG during childhood, associated or not with benign and malignant tumors. We screened DNA samples from blood or available tissues for probands and families’ members for DICER1variants using Next Generation Sequencing tools.

    Results:For all, DICER1pathogenic variants in RNaseIII and PAZ domains have been associated to thyroid pathologies during childhood. For 2 families the unique manifestation over generations was related to MNG. From 3 families, probands or relatives, positives for DICER1 mutation, developed differentiated thyroid cancer either PTC for one or FTC for 2. In 2 families, precocious clinical and molecular diagnosis accelerated diagnosis and management of other tumors as  pneumopleuroblastoma and  thyroid carcinoma.

    Discussion & Conclusion: Recurrence of MNG within a family or its association with children benign or malignant tumors should make them suspect of anomalies in the DICER1 protein as proposed in recent international recommendations. DTC seems to be elevated in this population. Early detection of DICER1 variants has important consequences in terms of therapeutic strategy, early tumours screening and genetic counselling.

 

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