Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor?
BACKGROUND
Conflicting data have been reported regarding the presence of a constitutive activation of Galphas 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 Galphas or Galphai are present in juvenile OGCTs and, if so, whether these mutations are significant prognostic factors.


METHODS
This was a multicentric nationwide study.


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
Galphas-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 Galphas exhibited a significantly more advanced tumor (P < 0.05) because seven of them (77.7%) were staged as Ic or had had a recurrence. Galphai did not exhibit any mutation.


CONCLUSIONS
Activating mutations of Galphas 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.
Kalfa
Nicolas
N
Unité d'Endocrinologie-Gynécologie Pédiatriques, Service de Pédiatrie 1, Hôpital Arnaud-de-Villeneuve, Hôpital Lapeyronie, Centre Hospitalier Universitaire Montpellier, 34295 Montpellier, France.
Ecochard
Aude
A
Patte
Catherine
C
Duvillard
Pierre
P
Audran
Francoise
F
Pienkowski
Catherine
C
Thibaud
Elisabeth
E
Brauner
Raja
R
Lecointre
Claudine
C
Plantaz
Dominique
D
Guedj
Anne-Marie
AM
Paris
Francoise
F
Baldet
Pierre
P
Lumbroso
Serge
S
Sultan
Charles
C
D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006106:Granulosa Cell Tumor / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D016612:Paraffin Embedding; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004247:DNA; D019205:GTP-Binding Protein alpha Subunits, Gs