DICER1 hotspot mutations in non-epithelial gonadal tumours

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Non-epithelial gonadal tumours include sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs).
• Specific somatic mutations in DICER1, a microRNA maturation gene, are linked to these tumours.
• Previous observations of DICER1 mutations in gonadal tumours warrant further investigation.

Purpose of the Study:

• To confirm, refine, and extend previous findings on DICER1 mutations in non-epithelial gonadal tumours.
• To investigate the frequency and location of DICER1 mutations in various gonadal tumour types.
• To explore the clinical implications of DICER1 mutations in tumour classification and treatment.

Main Methods:

• Sanger sequencing was used to analyze the RNase IIIa and IIIb domains of DICER1.
• 154 gonadal tumours (135 female, 19 male) and 43 extra-gonadal GCTs were analyzed.
• Matched constitutional DNA was used to confirm somatic mutations.

Main Results:

• Heterozygous non-synonymous DICER1 mutations were identified in 7.1% (14/197) of non-epithelial tumours, exclusively in the RNase IIIb domain.
• Mutations were most frequent in SCSTs (32%), particularly Sertoli-Leydig cell tumours (SLCTs) (8/15, >50%), and less common in gonadal GCTs (4.2%).
• No mutations were found in extra-gonadal GCTs or miscellaneous tumours; mutations affected only five specific residues and were confirmed as somatic.

Conclusions:

• DICER1 mutations are prevalent in the RNase IIIb domain of SLCTs but rare in GCTs.
• The identified genetic alterations in SLCTs could enhance tumour classification.
• These findings may pave the way for novel therapeutic strategies targeting DICER1 pathways in relevant cancers.