Molecular Pathogenesis of Granulosa Cell Tumors of the Ovary

Abstract

Granulosa cell tumors of the ovary (GCT) comprise a distinct subset of ovarian cancers that account for approximately 5% of all ovarian malignancies. They are thought to arise from normal proliferating granulosa cells of the late preovulatory follicle and exhibit many morphological and biochemical features of these cells. GCT are distinct from other ovarian carcinomas in their hormonal activity; their ability to secrete estrogen, inhibin, and Müllerian inhibiting substance accounts for some of the clinical manifestations of the disease and also provides useful tumor markers for disease surveillance. Although considered to be of low malignant potential, GCT are commonly associated with slow, indolent disease progression, and frequent yet long delays to tumor recurrence are characteristic of this disease. Unlike the more intensely investigated epithelial ovarian tumors, relatively little is known about the molecular and genetic changes that give rise to GCT. To date, many investigations have centered around pathways known to be involved in normal granulosa cell proliferation, including those activated by FSH receptor stimulation. Most recently, the finding that approximately 97% of adult GCT harbor a somatic missense mutation in the FOXL2 gene (c.402C→G; p.C134W) represents an exciting advancement in the field of GCT research. The high frequency with which the mutation occurs in adult GCT, along with its absence from juvenile GCT and other human malignancies is suggestive of an oncogenic or gain-of-function mutation and, indeed, that the mutation is pathognomonic for adult GCT. In this review, we explore the implications of this finding and the most recent work characterizing molecular pathways of potential pathogenetic significance in GCT.

Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential

“…Moreover, adult granulosa cell tumor (GCT) has recently been characterized by a single somatic missense mutation in the FOXL2 gene in human [31]. Since it is known that GCT can occurs also in the testes of juvenile and adult males [24,68], transdifferentiation in relation with FOXL2 action could take a place [44].…”

Precocious Puberty: Case Series

“…They are thought to arise from the granulosa cells of the ovary [8]. Granulosa cells constitute the somatic component of the ovarian follicle and function to produce sex steroids and other growth factors required for folliculogenesis and ovulation [6,8,11].…”

Genetics and genomics of ovarian sex cord‐stromal tumors

“…The cells contain hyperchromatic or markedly bizarre nuclei which lack the nuclear grooving characteristic of aGCT (2). Although the histologic appearances are therefore more 'aggressive' than for aGCT, the prognosis is generally better.…”