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High GATA-4 Expression Associates with Aggressive Behavior, whereas Low Anti-Müllerian Hormone Expression Associates with Growth Potential of Ovarian Granulosa Cell Tumors

Children’s Hospital and Program for Developmental and Reproductive Biology (M.A., M.H.), Biomedicum Helsinki, and Departments of Obstetrics and Gynecology (L.U.-K., A.L., R.B.) and Pathology (R.B.), University of Helsinki, 00014 Helsinki, Finland; and Department of Pediatrics (M.H.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Mikko Anttonen, M.B., Ph.D., Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. E-mail: mikko.anttonen{at}helsinki.fi.

Context: Granulosa cell tumors (GCTs) are ovarian malignancies that produce estrogens, inhibins, and anti-Müllerian hormone (AMH). The molecular pathogenesis of GCTs is likely to involve defects in the genes regulating normal granulosa cell proliferation during folliculogenesis.

Objective: The objective of this study was to test the role of factors regulating the normal granulosa cell function, i.e. AMH, inhibin-, SF-1 (steroidogenic factor-1), and GATA transcription factors in the pathobiology and clinical behavior of GCTs.

Design: We selected randomly a cohort of 80 GCT patients treated at our university hospital during 1971–2003, analyzed protein expression in the tumor samples embedded on a tissue microarray by immunohistochemistry, and correlated the data to clinical and histopathological parameters.

Results: We found no significant differences in the immunoreactivity levels of inhibin-, GATA-6, FOG-2 (friend of GATA-2), or SF-1 in GCTs compared with normal granulosa cells. AMH expression was, however, low (i.e. reduced) in 69% of GCTs and correlated inversely with tumor size (P = 0.0025). In contrast, GATA-4 expression was high (i.e. resembled normal granulosa cells) in 44% of GCTs and correlated positively with clinical stage and recurrence (P = 0.0232 and P = 0.0038, respectively). Fifty of the 80 patients had a follow-up for at least 10 yr, and 13 of them had recurrence(s). In multivariate analysis of recurrence, the high GATA-4 expression remained the only independent factor (risk ratio, 9.2; 95% confidence interval, 2.0–43.3; P = 0.0048).

Conclusions: The more aggressive GCTs retain a high GATA-4 expression, whereas the larger tumors lose the proliferation-suppressing AMH expression. The high GATA-4 expression in GCTs may serve as a marker of poor prognosis.

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