Pleuropulmonary Blastoma (PPB) Family Tumor and Dysplasia Syndrome, DICER1 Syndrome

DICER1 mutations are implicated in a broad range of tumors: pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian Sertoli-Leydig cell tumors (SLCTs), ciliary body medulloepithelioma (CBME) and other tumor types.

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DICER1 mutations are implicated in a broad range of tumors: pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian Sertoli-Leydig cell tumors (SLCTs), ciliary body medulloepithelioma (CBME) and other tumor types.

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Germline DICER1 haploinsufficiency predisposes to a broad range of tumors, most significantly pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian Sertoli-Leydig cell tumors (SLCTs), ciliary body medulloepithelioma (CBME), as well as various other tumor types. Collectively, this condition is called DICER1 syndrome, also previously known as "PPB family tumor and dysplasia syndrome." DICER1 mutations are inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.

The Ambry Test: Pleuropulmonary Blastoma-DICER1 detects mutations in the DICER1 gene by full gene sequence analysis of all coding domains and splice junctions. Identification of a DICER1 mutation can aid diagnosis and may dramatically improve outcome, particularly for pleuropulmonary blastoma (PPB), which can show significant clinical overlap with other types of lung cysts. DICER1 molecular testing is indicated in patients who are clinically suspected to have PPB, cystic nephroma, and ovarian Sertoli-Leydig tumors. 

Disease Name 
Pleuropulmonary Blastoma (PPB) Family Tumor and Dysplasia syndrome
DICER1 Syndrome
Disease Information 

The DICER1 gene encodes a dsRNA-specific ribonuclease (RNase) III endonuclease, which is required by the RNA interference (RNAi) pathway to produce the active small RNA component that represses gene expression. Germline DICER1 haploinsufficiency predisposes to a broad range of tumors, most significantly pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian Sertoli-Leydig cell tumors (SLCTs), ciliary body medulloepithelioma (CBME), as well as various other tumor types. Collectively, this condition is called DICER1 syndrome, also previously known as "PPB family tumor and dysplasia syndrome." DICER1 mutations are inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity. Heterozygous mutations of DICER1, with retention of the wild-type allele, have also been detected in a wide variety of cancer cells.1.2,3

Mutation of the DICER1 gene is found in approximately 50-70% of patients with PPB,1 and the prevalence of mutations in the other conditions may be considerable. Identification of a DICER1 mutation can aid diagnosis and management, particularly for PPB, which can show significant clinical overlap with other types of lung cysts.4 The range of different tumors that can occur in individuals with DICER1 mutations is broad, and it is likely that more associated tumors will be identified as further genetic testing is performed. 

Testing Benefits & Indication 

Identification of a DICER1 mutation can aid diagnosis and may dramatically improve outcome, particularly for pleuropulmonary blastoma (PPB), which can show significant clinical overlap with other types of lung cysts. DICER1 molecular testing is indicated in patients who are clinically suspected to have PPB, cystic nephroma, and ovarian Sertoli-Leydig tumors. DICER1 testing may also be considered for differential diagnosis, carrier testing for individuals with a family history, and for at risk pregnancies.

Test Description 

DICER1 coding exons1-26 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-26.Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing. Gross deletion/duplication analysis of DICER1 using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

50-75% of patients with pleuropulmonary blastoma (PPB) have a detectable mutation in the DICER1 gene (clinical sensitivity). Ambry DICER1 analysis (gene sequencing only) can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

 

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
5260 DICER1 gene sequencing and deletion/duplication analysis 14-21

 

Specialty 
Genes 
DICER1
Techniques 
References 

1. Slade I, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 2011;48(4):273 – 8. [PMID: 21266384]

2. Hill DA, et al. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009;325(5943):965. [PMID: 19556464]

3. Bahubeshi A, et al. Germline DICER1 mutations and familial cystic nephroma. J Med Genet. 2010;47(12):863 – 6. [PMID: 21036787]

4. Priest JR, et al. Pulmonary cysts in early childhood and the risk of malignancy. Pediatr Pulmonol. 2009;44(1):14 – 30. [PMID: 19061226]