The Oncogenic Roles of DICER1 RNase IIIb Domain Mutations in Ovarian Sertoli-Leydig Cell Tumors

Abstract

DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.

DICER1 hot‐spot mutations in ovarian gynandroblastoma

“…DICER1 is an endoribonuclease that controls the production of microRNAs; it remains unclear how DICER1 mutation drives the development of ovarian SLCT. We have reported previously that DICER1 mutation in SLCT was associated with the reduced expression of CYP19A1 (aromatase) that controls oestrogen synthesis from testosterone and differentiation of somatic cell lineages in the ovary . A recent report also confirmed that DICER1 mutation is associated with an increased testosterone level in patients with ovarian SLCT .…”

“…Recent studies have shown that approximately 95% of aGCTs harbour the p.C134W mutation in FOXL2 , while in‐frame duplications affecting the pleckstrin‐homology (PH) domain of AKT1 and/or activating AKT1 mutations were identified in 87.5% (14 of 16) of jGCTs in girls aged less than 15 years . Furthermore, approximately half or more of ovarian SLCTs harbour mutations in the RNase IIIb domain of DICER1 that skew the maturation of microRNAs . No FOXL2 p.C134W mutation was identified in seven ovarian gynandroblastomas analysed by Oparka et al .…”

DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry

“…The combination of these factors may be responsible for a stronger association between SLCT and DICER1 than was noted in previous reports. 11,15,34–36 None of the individuals with a centrally reviewed diagnosis of JGCT, steroid cell tumor, sex cord-stromal tumor with annual tubules or Sertoli cell tumor had germline DICER1 mutations, although one individual with a germline DICER1 mutation developed undifferentiated ovarian sarcoma and later SLCT. 37 …”

“…Mutations in DICER1 cause aberrant cleavage of mature 5p miRNAs resulting in altered expression of mRNAs with an accompanying risk for various types of neoplasms. 13,1718,19 Individuals with germline mutations in DICER1 are also at increased risk for several benign and malignant tumors including PPB, cystic nephroma and renal sarcoma, Wilms’ tumor, nodular thyroid hyperplasia and thyroid cancer, pineoblastoma and pituitary blastoma. 20–24,25–30 …”

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

“…However, in contrast to the classic model, the event on the second allele permits partial DICER1 function, barring a few exceptions (Brenneman et al, ). The RNase IIIb hotspot mutations interfere with DICER1's canonical processing of small regulatory RNAs from their hairpin‐shaped precursors resulting in an excess of 3p miRNAs and a deficiency of 5p miRNAs (Pugh et al, ; Rakheja et al, ; Seki et al, ; Wang et al, ).…”