The <i>FOXL2</i> Mutation (c.402C>G) in Adult-Type Ovarian Granulosa Cell Tumors of Three Japanese Patients: Clinical Report and Review of the Literature

Abstract

Adult-type granulosa cell tumor (AGCT) is a rare class of malignant ovarian tumor with unique features, characterized by slow growth, late recurrence, relatively good prognosis and unified cause in almost all patients. The forkhead box L2 (FOXL2) gene encodes an essential transcription factor in the ovary. FOXL2 is important in female sex determination, follicle recruitment, and granulosa cell development. About 70-97% of AGCTs were reported to carry a somatic mutation c.402C>G (C134W) in the FOXL2 gene. However, it is unknown whether AGCTs of Japanese patients harbor the FOXL2 c.402C>G mutation. Here, we report a mutational analysis of the FOXL2 gene in four Japanese patients with AGCTs, and we review the literature to determine the precise incidence of FOXL2 mutations in AGCTs. All four patients were analyzed by immunohistochemistry for FOXL2. Genomic DNA was extracted from paraffin-embedded tissues, and was analyzed to detect the c.402C>G mutation in FOXL2 by direct sequencing. All tumors were stained with FOXL2. Three of the four tumors harbor the c.402C>G mutation. Based on the literature review, FOXL2 immunostaining is a highly specific marker for sex cord-stromal tumors (SCSTs), but it is not specific for AGCTs, one subtype of SCSTs. We identified 340 patients with the FOXL2 mutation (c.402C>G) and determined that the incidence of the mutation is 91.9% in AGCT patients. Therefore, this FOXL2 mutation is specific to AGCTs in the ovary and is useful for diagnosis of this disease.

Aggressive adult granulosa cell tumor of the ovary without a FOXL2 mutation: A case report

“…DNA was extracted from both yellowish and necrotic portions in the formalin‐fixed paraffin‐embedded specimen. The design of primer sequences and PCR reactions was carried out as previously reported . The products were analyzed by Sanger sequencing.…”

“…The design of primer sequences and PCR reactions was carried out as previously reported. 7 The products were analyzed by Sanger sequencing. The FOXL2 point mutation (402C!G) could not be detected in either the yellowish or necrotic portion (Fig.…”

Foxl2 and Its Relatives Are Evolutionary Conserved Players in Gonadal Sex Differentiation

“…Among all these genes, Foxl2 has attracted particular attention during the last 15 years as a key player due to its involvement in sex differentiation and oogenesis [Baron et al, 2005;Benayoun et al, 2009;Veitia, 2010;Boulanger et al, 2014;Georges et al, 2014a;Nicol and Yao, 2014]. A substantial amount of information on FOXL2 action was initially acquired from studies in humans and other mammals, and many excellent reviews have already been published, most centered on the roles of FOXL2 in normal or pathological female development in mammals and/or vertebrates [Fuhrer, 2002;Baron et al, 2005;De Baere et al, 2005;Benayoun et al, 2009Benayoun et al, , 2010Beysen et al, 2009;Kobel et al, 2009;Pisarska et al, 2011;Uhlenhaut and Treier, 2011;Biason-Lauber, 2012;Caburet et al, 2012;Verdin and De Baere, 2012;Takahashi et al, 2013;Georges et al, 2014a;Rosario et al, 2014;Leung et al, 2016]. The present review focuses on ' foxl2 ' genes in light of recent findings on their evolution, expression, and roles in sex differentiation in animals.…”

Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management

“…50 Several studies have reported that approximately 70-97% of adult granulosa cell tumors carry a somatic c.402C>G missense point mutation in the FOXL2 gene. [51][52][53] The FOXL2 gene encodes a transcription factor that is expressed in different tissue types, including the ovaries and pituitary gland. This gene plays an essential role in ovarian development and differentiation.…”