Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Abstract

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

Genetics and Mutational Landscape of Ovarian Sex Cord-Stromal Tumors

“…These findings suggest that tumors harboring TP53 mutations may be a high-grade subgroup of aGCT. It is noteworthy however, that other studies have not observed mutations in TP53 at similar frequencies [2,88].…”

“…In a recent study by Pilsworth et al, the authors used a combination of whole genome sequencing and targeted sequencing [88], and reported a similar frequency of KMT2D inactivating mutations as that of the Hillman et al study [86] (10.8% compared to 13.9%). The difference between the two studies however was that in this study, there was no association of the KMT2D mutation with recurrence [88]. This is consistent with another published study [89] which also showed no association of this gene mutation with recurrent disease.…”

“…The low frequency of this mutation in these studies as well as our own, suggests that they may be pathogenic driver mutation in only a subset of aGCT. Additional inactivating mutations were also identified in low frequency, including the candidate tumor suppressor gene WNK2 and a newly discovered protein called NLRC5, which has been linked to the regulation of cancer immune evasion [88].…”

“…TERT has been reported to interact with major oncogenic signaling pathways including c-MYC, NFκB, and Wnt/β-catenin. Of these, activation of NFκB signaling has been reported in the KGN cell line [91,95] and p65 nuclear localization has been reported in GCT [96], although previous studies [85,86,88,90] have not identified mutations in these pathways.…”

FOXL2 in adult‐type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene?

“…The mice developed a highly penetrant phenotype of [6,23] AGCTs have a low mutation burden. If FOXL2 were a TSG, a higher mutational load would be expected [24] FOXL2 localisation and transactivation are not affected by C134W mutation in AGCTs [25] No FOXL2 cytoplasmic mislocalisation and protein aggregation [25] AGCT, adult-type granulosa cell tumour; BPES, blepharophimosis, ptosis, and epicanthus inversus syndrome; JGCT, juvenile granulosa cell tumour; OG, oncogene; TSG, tumour suppressor gene.…”