Activating mutations of the stimulatory G protein in juvenile ovarian granulosa cell tumors: A new prognostic factor?

Context: Conflicting data have been reported regarding the presence of a constitutive activation of G alpha s in ovarian granulosa cell tumors (OGCTs). Although the precise role of this mutation in the transformation of ovarian cells into malignant cells remains debatable, it has been demonstrated in other tissues that the rate of cell proliferation and invasiveness can be influenced by the gsp oncogene. Objective: The objective of this study was to determine whether activating mutations of G alpha s or G alpha i are present in juvenile OGCTs and, if so, whether these mutations are significant prognostic factors. Design and Setting: This was a multicentric nationwide study. Patients and Methods: Thirty children with juvenile OGCT were included from the malignant germinal tumor protocol of the French Society for Childhood Cancer. Genetic studies of the tumoral DNA used nested PCR, laser microdissection, and direct sequencing. Results: G alpha s-activating mutations in hot spot position 201 were found in nine patients (30%). Laser microdissection confirmed that mutations R201C and R201H were exclusively localized in the tumoral granulosa cells and were absent in the ovarian stroma. Patients with a hyperactivated G alpha s exhibited a significantly more advanced tumor (P < 0.05) because seven of them (77.7%) were staged as Ic or had had a recurrence. G alpha i did not exhibit any mutation. Conclusions: Activating mutations of G alpha s are present in 30% of juvenile OGCTs. The gsp oncogene, which is known to be implicated in cell proliferation and tumoral invasiveness, can be considered as a new prognostic factor of these tumors.