HER2 and GATA4 are new prognostic factors for early‐stage ovarian granulosa cell tumor—a long‐term follow‐up study

Abstract

Granulosa cell tumors (GCTs) carry a risk of recurrence also at an early stage, but reliable prognostic factors are lacking. We assessed clinicopathological prognostic factors and the prognostic roles of the human epidermal growth factor receptors (HER 2–4) and the transcription factor GATA4 in GCTs. We conducted a long-term follow-up study of 80 GCT patients with a mean follow-up time of 16.8 years. A tumor-tissue microarray was immunohistochemically stained for HER2–4 and GATA4. Expression of HER2–4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization. The results were correlated to clinical data on recurrences and survival. We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%. Tumor recurrence was detected in 24% of the patients at a median of 7.0 years (range 2.6–18 years) after diagnosis. Tumor stage was not prognostic of disease-free survival (DFS). Of the molecular prognostic factors, high-level expression of HER2, and GATA4, and high nuclear atypia were prognostic of shorter DFS. In multivariate analyses, high-level coexpression of HER2 and GATA4 independently predicted DFS (hazard ratio [HR] 8.75, 95% CI 2.20–39.48, P = 0.002). High-level expression of GATA4 also predicted shorter DSS (HR 3.96, 95% CI 1.45–12.57, P = 0.006). In multivariate analyses, however, tumor stage (II–III) and nuclear atypia were independent prognostic factors of DSS. In conclusion HER2 and GATA4 are new molecular prognostic markers of GCT recurrence, which could be utilized to optimize the management and follow-up of patients with early-stage GCTs.

FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development

“…GATA4 is also present in hAGCTs (33,34,87) and appears to synergize with SMAD3 to promote tumor cell proliferation (33). Thus, GATA4 also appears to be a marker of AGCTs (88). Western blot analyses confirmed reduced expression of FOXO1 and PTEN in tumors of the Foxo1/3/Pten mice compared with ovaries in control mice (Figure 8).…”

Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors

“…Tumor size, tumor rupture, presence of residual tumor, incomplete staging, and even body mass index and diabetes have been suggested as clinical prognostic factors for recurrence [9,10,[15][16][17][18][19]. Histopathologic and molecular prognosticators have included nuclear atypia, mitotic rate, diffuse growth pattern and expression of transcription factor GATA4 and human epidermal growth factor receptor HER2 [12,13,18,20,21]. Most of these studies Gynecologic Oncology 143 (2016) [571][572][573][574][575][576][577] have, nonetheless, lacked the diagnostic validation of tumors with FOXL2 mutation status and suffered from either small number of patients or relatively short follow-up periods [4,14,16,19,20].…”

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

“…Also HER4 alterations have been found in breast cancer (Yarden & Pines 2012). We found that high-level ErbB2/HER2 protein expression in GCTs associates with tumor recurrence and is prognostic for shorter disease-free survival, while ErbB3 and ErbB4 expression did not correlate with the clinical characteristics of GCT patients (Färkkilä et al 2014).…”