DICER1 (Dicer 1 Ribonuclease III)

Our study demonstrates that the majority (86%) of SLCTs with heterologous RMS harbor double DICER1 mutations (a hotspot mutation and a nonsense or frameshift loss-of-function mutation), supporting the existing knowledge on DICER1 mutations associated with RMS heterologous elements, the presence of which should trigger genetic counselling. Our findings also suggest that molecular alterations other than DICER1, namely, TERT promoter and TP53 mutations, may contribute to component-specific oncogenic transformation.

Prognosis correlates with differentiation and stage. Periodically, clinical and biochemical surveillance is advised, and molecular testing can guide genetic counseling and further management.

A high prevalence of DICER1 germline variants was observed in patients with PPB, consistent with previous studies. Family history alone may be insufficient to suspect DICER1 syndrome, and thus, proactive genetic testing of family members is advisable in all cases of PPB.

DICER1 mutations are frequently detected in pediatric PPB, CN, SCST, ASK, nodular thyroid goiter, thyroid adenoma, and genitourinary rhabdomyosarcoma, which often represent as the index case of DICER1 syndrome. Performing DICER1 mutation testing in these patients not only facilitates tumor diagnosis and secondary cancer surveillance, but also enables the comprehensive genetic risk assessment and management for patient's family members.

There is no published guidance for recurrent NCMH at the olfactory groove/cribriform plate region. Conservative local excisions should be pursued for tumor recurrences.

Notably, the presence of cartilage foci within a RMS-like neoplasm represents a strong clue to an underlining DICER1 alteration. The rarity of this presentation in the nasal fossa at this age, coupled with its implications for diagnosis, treatment, and familial screening, emphasizes the need for awareness of the morphology patterns of DICER1-associated neoplasms across diverse anatomical sites.

Epigenetically defined PB subtypes are characterized by distinct genetic events. Frequent gains of the oncogene OTX2 indicate a role in the pathogenesis of PB independent of its subtype.

Moreover, activity assays, RNA-seq data, and Argonaute-mRNA profiling, confirm that these confer increased repression capacity. These data expand the molecular consequences of Dicer1 hotspot mutations in cancer.

Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG/AMP gene-specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence (PS3) code.

The present study confirms that SCSTs classified as AGCTs differ from their ovarian counterparts in that they largely lack FOXL2 mutations.

One patient had pleomorphic Sertoli cells associated with TP53 variants and very poor prognosis with early recurrence after complete initial surgery of a stage IA tumor. These data highlight the biological relationship between SLCTs and their heterologous elements, and the clinical usefulness of identifying pathogenic variants (ie, TERT and TP53), although this last point needs to be confirmed in a larger series.