DICER1 – DICER1-related Tumor Predisposition Syndrome

DICER1-related tumor predisposition syndrome is an autosomal dominant, pleiotropic cancer predisposition disorder characterized by both benign and malignant neoplasms, including pleuropulmonary blastoma, cystic nephroma, ovarian Sertoli-Leydig cell tumors, multinodular goiter, embryonal rhabdomyosarcoma, and differentiated thyroid carcinoma (PMID:21205968). Germline loss-of-function DICER1 mutations truncate the RNase IIIb domain, while tumor-specific somatic “hotspot” missense mutations in the metal-binding residues of RNase IIIb (e.g., p.Asp1709Gly, p.Asp1810Tyr) disrupt miRNA processing, establishing a two-hit mechanism (PMID:22187960).

Inheritance is autosomal dominant with reduced penetrance. Familial aggregation across >10 kindreds and segregation of pathogenic alleles in at least 25 affected relatives support this mode of transmission (PMID:25451712). A recurrent germline nonsense variant, c.3540C>A (p.Tyr1180Ter), has been reported in exon 21 in multiple families, underscoring the role of truncating mutations in disease initiation (PMID:25451712).

The variant spectrum includes truncating (nonsense, frameshift), splice-site, and deep-intronic alleles leading to loss of RNase IIIb catalytic residues, as well as recurrent somatic missense mutations at codons E1705, D1709, G1809, D1810, and E1813. Case series have described biallelic DICER1 mutations in pleuropulmonary blastoma, cystic nephroma, and rhabdomyosarcoma, consistent with neomorphic RNase IIIb activity in tumorigenesis (PMID:24675358).

Functional studies demonstrate that RNase IIIb hotspot mutants selectively impair 5p miRNA strand cleavage while preserving 3p strand generation, leading to global shifts in miRNA homeostasis and derepression of cell cycle and developmental pathways (PMID:23132766). In vitro expression of DICER1 RNase IIIb mutants in human granulosa or stem cell lines promotes proliferation and aberrant differentiation, aligning with the tumor spectrum of DICER1 syndrome (PMID:26408257).

No compelling conflicting evidence disputes the role of DICER1 in this syndrome. The robust genetic, segregation, and experimental concordance over >10 years of study fulfill criteria for a definitive gene–disease relationship.

Key Take-home: Pathogenic DICER1 variants define a clinically actionable autosomal dominant tumor predisposition syndrome warranting genetic testing and tailored surveillance.

References

• JAMA • 2011 • DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors PMID:21205968
• N Engl J Med • 2012 • Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers PMID:22187960
• The Journal of pathology • 2013 • Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias PMID:23132766
• Cancer research • 2014 • Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma PMID:24675358
• Neoplasia • 2015 • The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors PMID:26408257
• European journal of medical genetics • 2014 • DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter PMID:25451712

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