Genetics and Mutational Landscape of Ovarian Sex Cord-Stromal Tumors

Abstract

Ovarian sex cord-stromal tumors (SCST) are uncommon tumors accounting for approximately 8% of all ovarian malignancies. By far, the most common are granulosa cell tumors (GCT) which represent approximately 90% of SCST. SCST are also found in the hereditary syndromes: Peutz-Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Key genomic and genetic events contributing to their pathogenesis have been the focus of recent studies. Most of the genomic studies have been limited to GCT which have identified a number of recurring chromosomal abnormalities (monosomy and trisomy), although their contribution to pathogenesis remains unclear. Recurrent DICER1 mutations are reported in non-hereditary cases of Sertoli cell and Sertoli–Leydig cell tumors (SLCT), while recurrent somatic mutations in both the juvenile (jGCT) and adult forms of GCT (aGCT) have also been reported. Approximately 30% of jGCT contain a somatic mutation in the gsp oncogene, while a further 60% have activating mutations or duplications in the AKT gene. For aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in the majority of tumors (primary and recurrent), arguably defining the disease. A further mutation in the human telomerase promoter appears to be an important driver for recurrent disease in aGCT. However, despite several studies involving next generation sequencing, the molecular events that determine the stage, behavior and prognosis of aGCT still remain to be determined. Further, there is a need for these studies to be expanded to other SCST in order to identify potential targets for personalized medicine.