Understanding DICER1 Mutations: A Key Player in Pediatric Tumor Predisposition Syndromes

Introduction

DICER1 is a gene that plays a crucial role in microRNA (miRNA) processing and, by extension, the regulation of gene expression. Germline mutations in DICER1 cause DICER1 syndrome, a rare autosomal dominant hereditary cancer predisposition syndrome primarily affecting children and young adults. Recognizing the clinical spectrum of DICER1-related disorders is essential for early detection, surveillance, and genetic counseling.

What is the DICER1 Gene?

The DICER1 gene encodes a ribonuclease (RNase) enzyme that is integral to the biogenesis of miRNAs. These small non-coding RNAs regulate gene expression by silencing target messenger RNAs (mRNAs). Mutations in DICER1 disrupt this critical post-transcriptional regulation, leading to dysregulation of numerous pathways involved in cellular proliferation and apoptosis (Foulkes et al., 2014).

Tumorigenesis in DICER1 syndrome often follows a two-hit hypothesis: the first hit is a germline loss-of-function mutation, and the second hit is typically a somatic "hotspot" missense mutation in the RNase IIIb domain of the protein. This combination leads to partial loss of function and contributes to tumor formation (Angeles et al., 2020).

What is DICER1 Syndrome?

DICER1 syndrome is a tumor predisposition disorder characterized by a spectrum of rare, mostly benign tumors and several malignancies, particularly during childhood. It was first recognized in association with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor. The syndrome has since expanded to include a broader tumor spectrum.

Associated Tumors and Conditions

The tumors and cystic lesions associated with DICER1 mutations include:

• Pleuropulmonary blastoma (PPB) – the sentinel tumor, often presenting in infancy or early childhood

• Cystic nephroma – benign kidney tumor seen in early childhood

• Sertoli-Leydig cell tumors of the ovary – a sex cord-stromal tumor, often in adolescent females

• Thyroid nodules and differentiated thyroid cancer

• Nasal chondromesenchymal hamartoma

• Medulloepithelioma – a rare ocular tumor

• Embryonal rhabdomyosarcoma, especially of the cervix or uterus

Not every individual with a DICER1 mutation will develop a tumor, and penetrance is variable. However, identifying mutation carriers allows for early screening and intervention (Schultz et al., 2018).

Diagnosis and Genetic Testing

Diagnosis begins with suspicion based on clinical or family history. Genetic testing for DICER1 mutations is recommended for individuals with any associated tumor or those with a family history of DICER1-related cancers. Once a germline mutation is confirmed, cascade testing for family members is advised.

Importantly, not all variants are pathogenic; variant interpretation requires caution and often expert consultation. Germline testing should be done in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab and followed with appropriate counseling.

Surveillance and Management

While no universal screening guidelines exist, proposed surveillance strategies include:

• Chest imaging (X-ray or CT) during early childhood to monitor for PPB

• Renal ultrasound in young children to detect cystic nephroma

• Thyroid ultrasound starting in early adolescence

• Pelvic ultrasound for adolescent females at risk of ovarian tumors

• Continued surveillance into adulthood for thyroid and other neoplasms

  
  

Given the diversity of associated tumors, care is best coordinated through a multidisciplinary team including oncologists, geneticists, endocrinologists, and surgeons. Risk-reducing surgery is not commonly pursued due to the typically benign and treatable nature of most DICER1-related tumors.

Psychosocial and Family Considerations

DICER1 syndrome often affects multiple generations, and understanding inheritance is critical for families. A 50% chance exists that a mutation will be passed from a parent to a child. Genetic counseling helps families understand these risks, make informed decisions, and implement appropriate surveillance protocols. The emotional burden of cancer risk in children can be substantial, underscoring the need for supportive care.

Conclusion

DICER1 mutations reveal the intricate interplay between genetics, tumor development, and personalized medicine. Though rare, DICER1 syndrome offers a powerful example of how early genetic recognition can lead to proactive care, early tumor detection, and improved outcomes. As our understanding of tumor predisposition syndromes grows, so does the importance of integrating genomics into routine pediatric and adolescent care.

References

Angeles, D. C., Montalbano, A., & Malkin, D. (2020). DICER1 syndrome: A primer for clinicians. European Journal of Medical Genetics, 63(9), 103888. https://doi.org/10.1016/j.ejmg.2020.103888

Foulkes, W. D., Priest, J. R., & Duchaine, T. F. (2014). DICER1: Mutations, microRNAs and mechanisms. Nature Reviews Cancer, 14(10), 662–672. https://doi.org/10.1038/nrc3795

Schultz, K. A. P., Harris, A. K., Finch, M., Mertens, A. C., & Hill, D. A. (2018). DICER1 tumor predisposition syndrome: A clinical and molecular review. Current Opinion in Pediatrics, 30(6), 750–756. https://doi.org/10.1097/MOP.0000000000000691

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