Abstract
BackgroundOvarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression.MethodsWe have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes.ResultsOur results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related.ConclusionsOur combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1283-0) contains supplementary material, which is available to authorized users.
Highlights
Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors
Identification of putative drivers: recurrently broken, amplified/duplicated or deleted genes To further exploit our comparative genomic hybridization (CGH) and transcriptomic data, we focused on small-scale rearrangements that might help us pinpoint candidate genes whose duplication, deletion or breakage might be involved in tumorigenesis
In conclusion, our analysis identifies candidate co-driver genes, whose various alterations could contribute to GCT pathogenesis besides the FOXL2 somatic mutation
Summary
Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors, and account for more than 5% of ovarian cancers [1]. Various studies have revealed that a somatic mutation leading to the p.C134W substitution in the transcription factor FOXL2 appears in > 95% of adult-type GCTs [4]. FOXL2 with SMAD3 [5] and FOXL2 activity in other systems [6] This variant is deficient in its ability to promote apoptosis [7] and displays a mild loss-of-function on targets involved in cell cycle and DNA-damage repair [8]
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