Objectives Sertoli-Leydig and granulosa cell tumors are sex cord-stromal tumors of the ovary that primarily impact young women. Adult-type granulosa cell tumors (aGCTs) are characterized by pathognomonic somatic FOXL2 mutations, whilst 30–60% of Sertoli-Leydig cell tumors (SLCTs) harbor DICER1 mutations. A comprehensive assessment of the repertoire of genomic alterations of sex cord-stromal tumors has yet to be performed.
Methods Primary SLCTs (n=2), juvenile (j)GCTs (n=2) and a primary and matched mixed SLCT/aGCT recurrence (n=2) were subjected to whole-exome sequencing. Somatic mutations and copy number alterations were defined using state-of-the-art bioinformatics algorithms.
Results Ovarian sex cord-stromal tumors displayed a low mutational burden, with a median of 22 (range 13–82) somatic mutations. Mutational analysis revealed the presence of a DICER1 p.R293lfs*4 frameshift mutation in the pure SLCT. A FOXL2 p.C134W hotpot mutation was identified in the primary and recurrent mixed SLCT/aGCT; in addition, LAMA5, ZNF837, and HCFC1 missense mutations and an UBR2 splice-site mutation were present only in the mixed recurrence but absent in the primary mixed SLCT/aGCT. Neither of the two jGCTs harbored FOXL2 or DICER1 mutations, and none of the identified somatic mutations and copy number alterations were shared between the two jGCTs. jGCT1 harbored GATA4 p.L281M/Q missense mutations and copy number gains of chromosomes 4 and 8, whereas jGCT2 displayed a TOPAZ1 p.K335R missense mutation and chromosome 12 and 18 gains.
Conclusions Sex cord-stromal tumors are a genetically heterogeneous group of rare ovarian neoplasms. Larger studies to assess whether jGCTs harbor recurrent genetic/epigenetic alterations are warranted.
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