A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

Abstract

Key Points Question What are the prevalence, risk, and phenotypic spectrum of individuals with a germline putative loss-of-function (pLOF) variant in DICER1 according to a genome-first approach in a population-scale cohort? Findings In this cohort study, DICER1 pLOF variants were more than twice as common (even after adjustment for relatedness) than previously observed. Malignant tumors were observed in 16% of participants with a DICER1 pLOF variant, which is comparable to the frequency of neoplasms in the largest phenotype-first DICER1 studies published to date. Meaning The genome-first approach complements more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation in monogenic disorders.

Sex Bias in Differentiated Thyroid Cancer

“…It is proposed that a male patient with a thyroid cancer or even a multinodular goiter, especially early in life, should be proposed a search for DICER syndrome [ 40 ], which illustrates the combining effect of the gender bias and of the genetic tumor predisposition. Another study starting from search for DICER1 variants in the population found the same number of thyroid cancers in males and females (one for each sex) among carriers of pathogenic variants [ 41 ].…”

Prevalence of Pathogenic Germline DICER1 Variants in Young Individuals Thyroidectomised Due to Goitre – A National Danish Cohort

“…( 20 ) demonstrated that poorly differentiated thyroid carcinomas in children and adolescents are strongly associated with DICER1 mutations and are highly aggressive, although in most cases differentiated thyroid carcinomas in DICER1 patients behave in an indolent manner ( 20 ). A genome-first approach study of the DICER1 observed that individuals harbouring putative LOF variants of DICER1 had a significantly stronger association with thyroid cancer and thyroidectomy compared to matched controls without DICER1 variations ( 21 ). These findings suggest considerations of early total thyroidectomy in a DICER1 patient - when goitre is detected - is relevant.…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Culturing normal HSPCs with MSCs from these mutant mice resulted in altered hematopoietic cell function and morphology, while normal hematopoiesis ensued after the transplantation of bone marrow HSPCs from the mutant mice into wild-type murine recipients [ 280 ]. In contrast to these murine studies, recent research on the initiation of MDS in humans was not found to be associated with pathogenic germline DICER1 variants [ 281 , 282 ]. Studies by Balderman et al [ 283 ], using a transgenic murine MDS model, further support the concept of an altered bone marrow microenvironment contributing to myeloid skewing during MDS progression.…”