Gs alpha overexpression and loss of Gs alpha imprinting in human somatotroph adenomas: association with tumor size and response to pharmacologic treatment.

ABSTRACT

Gs alpha, the alpha-subunit of the heterotrimeric GTP-binding protein, is coded from the GNAS gene, which is imprinted in a tissue-specific manner. Gs alpha is paternally silenced in normal pituitary, but Gs alpha imprinting relaxation is found in some tumoral tissue. In addition, Gs alpha mRNA levels are high in some somatotroph adenomas not bearing the active Gs alpha mutant, the gsp oncogene. In this study, the impact of loss of imprinting on Gs alpha expression level and on tumoral phenotype has been investigated. We compared the expression and imprinting of 4 transcripts of GNAS locus (NESP55, XL alpha s, exon 1A, Gs alpha) of 60 somatotroph adenomas with those of 23 lactotroph adenomas. The paternal and maternal transcripts were quantified using allele-specific real-time PCR and FokI polymorphism. Moreover, the methylation of exon 1A DMR was analyzed. As is the case for the gsp oncogene, high Gs alpha expression in gsp- tumors was associated with smaller tumor size and better octreotide sensitivity. A strong imprinting relaxation (percentage of paternal Gs alpha expression >or=7.5%) was found only in gsp- tumors. The loss of Gs alpha imprinting was associated with a decrease in exon 1A mRNA expression. Unexpectedly, the methylation status of exon 1A DMR was not modified in relaxed tumors. Maternal Gs alpha mRNA level decreased with exon 1A level, and consequently the loss of Gs alpha imprinting did not induce the expected Gs alpha overexpression. Finally, XL alpha s mRNA level correlated with that of paternal Gs alpha and of NESP55 showing the complexity of gene regulation in the GNAS locus.