DICER1-Associated Tumor Genetics and Pathophysiology

DICER1 encodes an RNase III endoribonuclease critical for the biogenesis of microRNAs, small regulatory RNAs that fine-tune gene expression. Germline loss-of-function mutations in DICER1 underlie an autosomal dominant tumour predisposition syndrome, characterised by a remarkable spectrum of neoplasms, often presenting in childhood. Tumours typically arise through a two-hit mechanism in which an inherited truncating mutation is followed by a somatic ‘hotspot’ neomorphic mutation in the RNase IIIb domain. The timing and combination of these events influence tissue-specific phenotypes, driving pleuropulmonary blastoma in the lung, Sertoli–Leydig ovarian tumours, cystic nephroma of the kidney and various sarcomas. Pathophysiologically, recurrent molecular alterations such as global hypomethylation and additional cooperating mutations contribute to lineage-specific differentiation and tumour progression. Improved molecular classification and mechanistic insights are guiding surveillance strategies, risk assessment and the development of targeted therapeutic approaches.

Research from Nature Portfolio

Genomic profiling of DICER1-associated neoplasms has delineated three distinct molecular classes of mesenchymal tumours, each defined by shared mutational and epigenetic signatures. The first class comprises low-grade mesenchymal tumours with DICER1 alterations, typified by moderate cellularity and indolent behaviour. The second encompasses high-grade sarcomas enriched for additional driver mutations, displaying aggressive clinical features. The third class, primary intracranial sarcoma with DICER1 alteration, is distinguished by unique central nervous system tropism and specific methylation patterns. These findings have refined diagnostic categories, enabling more precise prognostication and laying the foundation for future trials of epigenetic or mutation-targeted therapies.

DICER1-Associated Tumor Genetics and Pathophysiology publication trend

The graph below shows the total number of articles in dicer1-associated tumor genetics and pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

DICER1: Gene encoding an endoribonuclease that processes precursor RNAs into mature microRNAs.

microRNA (miRNA): Small non-coding RNA that modulates gene expression by guiding repression complexes to target mRNAs.

Germline mutation: Heritable alteration present in every cell, inherited or arising in gametes.

Somatic mutation: Genetic change acquired in non-germ cells, restricted to tumour tissue.

Neomorphic mutation: Variant that imparts a novel or abnormal function to a protein domain.

Two-hit tumour suppression model: Concept that biallelic inactivation of a tumour suppressor gene is essential for malignant transformation.

References

1. Genomic characterization of DICER1-associated neoplasms uncovers molecular classes. Nature Communications (2023).
2. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model. F1000Research (2018).
3. DICER1 Syndrome: DICER1 Mutations in Rare Cancers. Cancers (2018).
4. Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup. Modern Pathology (2021).
5. Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group. Familial Cancer (2021).