Predictors of Recurrence of Ovarian Granulosa Cell Tumors

Nosov, Vladimir; Silva, Ivaldo; Tavassoli, Fattaneh A.; Adamyan, L. V.; Farias‐Eisner, Robin; Schwartz, Peter E.

doi:10.1111/igc.0b013e3181a48a6f

Cited by 28 publications

(20 citation statements)

References 27 publications

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“…It has been reported that patients with adult granulosa cell tumors containing a nongranulosa sex-cord component are associated with better disease-free survival. 22 Although we could not find any survival differences between tumors with and without non-granulosa sex-cord component, our findings suggest, together with those in the literature, that adult granulosa cell tumors with a different sex-cord component may represent a distinct clinicopathologic form with more favorable prognosis.…”

Section: Discussioncontrasting

confidence: 62%

“…Some assessed clinical parameters such as age at diagnosis, tumor size, surgical stage, serum tumor markers, tumor rupture during surgery, and adjuvant chemotherapy after the initial surgery. 3,6,9,[19][20][21][22] Others analyzed pathologic features such as cellular atypia, mitotic index, histologic subtype, presence of Call-Exner bodies, and tumor cell luteinization. 20,22 In our series, none of the clinical and pathologic features we analyzed correlated with outcome.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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Recently, mutation of the FOXL2 gene has been consistently identified in adult granulosa cell tumors of the ovary. The purpose of this study is to investigate whether the FOXL2 mutation and mRNA expression have a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. Thirty-four adult granulosa cell tumors and 20 juvenile granulosa cell tumors were examined for the presence of the FOXL2 (C402G) mutation. Expression levels were studied by quantitative PCR and immunohistochemistry. We found that FOXL2 (C402G) mutation was present in 19/27 (70%) of the adult type tumors but in none of the juvenile granulosa cell tumors (0/18). No correlation was encountered between the presence of FOXL2 mutation and various clinicopathologic parameters except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 (C402G) mutation had a worse disease-free survival than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in both adult and juvenile granulosa cell tumors. We also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein, and there was a linear correlation between mRNA and immunohistochemical FOXL2 expression in both adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall survival and disease-free survival than those with negative or weakly immunoreactive tumors. Our data suggest that FOXL2 mutation and mRNA expression are of prognostic importance in both adult and juvenile granulosa cell tumors.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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“…7 For the tumor size, a cutoff of tumor diameter 10 cm was chosen based on earlier GCT studies. [39][40][41] For controls, we utilized three normal ovarian tissue samples from three pre-menopausal women operated upon for cervical cancer. From July 2008 to December 2010, we obtained 10 fresh tumor samples (7 primary and 3 recurrent GCTs) for primary cell cultures (see below).…”

Section: Materials and Methods Human Tissue Samplesmentioning

confidence: 99%

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

Anttonen

Färkkilä

Tauriala

et al. 2011

Laboratory Investigation

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Ovarian granulosa cell tumors (GCTs) are sex cord stromal tumors that constitute 3-5% of all ovarian cancers. GCTs usually present with an indolent course but there is a high risk of recurrence, which associates with increased mortality, and targeted treatments would be desirable. Anti-Mü llerian hormone (AMH), a key factor regulating sexual differentiation of the reproductive organs, has been implicated as a growth inhibitor in ovarian cancer. GCTs and normal granulosa cells produce AMH, but its expression in large GCTs is usually downregulated. Further, as the lack of specific AMHsignaling pathway components leads to GCT development in mice, we hypothesized that AMH inhibits growth of GCTs. Utilizing a large panel of human GCT tissue samples, we found that AMH type I receptors (ALK2, ALK3 and ALK6) and type II receptor (AMHRII), as well as their downstream effectors Smad1/5, are expressed and active in GCTs. AMHRII expression was detected in the vast majority (96%) of GCTs and correlated with AMH mRNA and protein expression. AMH mRNA level was low in large GCTs, confirming previous findings on low-AMH protein expression in large human as well as mouse GCTs. To study the functional role of AMH in this peculiar ovarian cancer, we utilized a human GCT cell line (KGN) and 10 primary GCT cell cultures. We found that the AMH-Smad1/5-signaling pathway was active in these cells, and that exogenous AMH further activated Smad1/5 in KGN cells. Furthermore, AMH treatment reduced the number of KGN cells and primary GCT cells, with increasing amounts of AMH leading to augmented activation of caspase-3 and subsequent apoptosis. All in all, these data support the premise that AMH is a growth inhibitor of GCTs.

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“…Total EGFR protein expression in GCT tissue samples and in GCT cell lines, the KGN and COV434, has been demonstrated earlier (Leibl et al 2006, Nosov et al 2009, Zhang et al 2010, Jamieson & Fuller 2012, Nofech-Mozes et al 2012, Wang et al 2012. In primary and recurrent GCTs, EGFR expression localizes to the cell membrane and cytoplasm (Leibl et al 2006, Nosov et al 2009, Nofech-Mozes et al 2012, Wang et al 2012 and has been suggested to predict GCT recurrence.…”

Section: Introductionmentioning

confidence: 97%

“…In primary and recurrent GCTs, EGFR expression localizes to the cell membrane and cytoplasm (Leibl et al 2006, Nosov et al 2009, Nofech-Mozes et al 2012, Wang et al 2012 and has been suggested to predict GCT recurrence. In this study, we further analyzed the expression pattern of the phosphorylated, active form of EGFR protein in our GCT tissue microarray.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

Andersson¹,

Anttonen²,

Färkkilä³

et al. 2014

Journal of Molecular Endocrinology

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Epidermal growth factor receptor (EGFR) is implicated in the progression of many human cancers, but its significance in ovarian granulosa cell tumor (GCT) pathobiology remains poorly understood. We assessed the EGFR gene copy number, surveyed the mRNA and protein expression patterns of EGFR in 90 adult GCTs, and assessed the in vitro sensitivity of GCTcells to EGFR inhibition. Low-level amplification of EGFR gene was observed in five GCTs and highlevel amplification in one sample. EGFR mRNA was robustly expressed in GCTs. Most tumors expressed both unphosphorylated and phosphorylated EGFR protein, but the protein expression did not correlate with clinical parameters, including the risk of recurrence. Smallmolecule EGFR inhibitors reduced the EGF-induced activation of EGFR and its downstream signaling molecules at nanomolar doses, but cell viability was reduced, and caspase-3/7 was activated in GCTcells only at micromolar doses. Based on the present results, EGFR is active and abundantly expressed in the majority of GCTs, but probably has only minor contribution to GCT cell growth. Given the high doses of EGFR inhibitors required to reduce GCT cell viability in vitro, they are not likely to be effective for GCT treatment as single agents; they should rather be tested as part of combination therapies for these malignancies.

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Predictors of Recurrence of Ovarian Granulosa Cell Tumors

Cited by 28 publications

References 27 publications

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

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