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Intronic Germline DICER1 Variants in Patients With Sertoli-Leydig Cell Tumor
Claudette R Fraire1, Paige R Mallinger2,3,4, Jessica N Hatton5
1Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX.
JCO Precision Oncology
|October 26, 2023
Summary
Germline DICER1 pathogenic loss-of-function variants predispose individuals to cancers like Sertoli-Leydig cell tumors (SLCT). Novel intronic variants affecting splicing were identified in SLCT patients lacking typical DICER1 variants, suggesting broader diagnostic approaches.
Area of Science:
- Genetics and Oncology
- Molecular Biology
- Cancer Predisposition Syndromes
Background:
- Germline pathogenic loss-of-function (pLOF) variants in DICER1 are linked to various solid neoplasms, including Sertoli-Leydig cell tumors (SLCT).
- Common DICER1 pLOF variants include frameshift indels and nonsense or splice-site altering base substitutions.
- Some patients with DICER1-associated tumors lack detectable germline or tumor pLOF variants.
Purpose of the Study:
- To investigate the genetic basis of SLCT in patients without detectable germline DICER1 pLOF variants.
- To identify novel DICER1 variants that may contribute to tumorigenesis.
- To evaluate the utility of intronic variant and splicing analysis in diagnosing DICER1-related cancers.
Main Methods:
- Tumor sequencing was performed on two patients with SLCT.
- Conventional exon-directed germline sequencing was conducted.
- A custom capture panel was used for comprehensive DICER1 variant analysis, including intronic regions.
- Splicing analysis was performed to assess the functional impact of identified variants.
Main Results:
- Two patients with SLCT harbored only somatic missense DICER1 RNase IIIb variants in their tumors.
- No exonic pLOF variants were detected in the germline of these patients via conventional sequencing.
- Novel intronic variants (c.1752+213A>G and c.1509+16A>G) affecting DICER1 splicing were identified using a custom capture panel.
Conclusions:
- Somatic missense DICER1 variants and novel intronic variants impacting splicing can contribute to SLCT development.
- Conventional germline sequencing may miss pathogenic DICER1 variants in patients with DICER1-associated tumors.
- Intron sequencing and splicing analysis are recommended when no exonic DICER1 pLOF variants are found despite strong clinical suspicion for DICER1-related cancers.
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