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Gsα overexpression and loss of Gsα imprinting in human somatotroph adenomas: Association with tumor size and response to pharmacologic treatment
Author(s) -
Picard Christophe,
Silvy Monique,
Gerard Corinne,
Buffat Christophe,
Lavaque Esteban,
FigarellaBranger Dominique,
Dufour Henri,
Gabert Jean,
Beckers Albert,
Brue Thierry,
Enjalbert Alain,
Barlier Anne
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22816
Subject(s) - gnas complex locus , genomic imprinting , biology , exon , g alpha subunit , gs alpha subunit , microbiology and biotechnology , methylation , endocrinology , medicine , dna methylation , gene expression , gene , protein subunit , genetics , adenylyl cyclase , stimulation
Gsα, the α‐subunit of the heterotrimeric GTP‐binding protein, is coded from the GNAS gene, which is imprinted in a tissue‐specific manner. Gsα is paternally silenced in normal pituitary, but Gsα imprinting relaxation is found in some tumoral tissue. In addition, Gsα mRNA levels are high in some somatotroph adenomas not bearing the active Gsα mutant, the gsp oncogene. In this study, the impact of loss of imprinting on Gsα expression level and on tumoral phenotype has been investigated. We compared the expression and imprinting of 4 transcripts of GNAS locus (NESP55, XLαs, exon 1A, Gsα) 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 Gsα expression in gsp ‐ tumors was associated with smaller tumor size and better octreotide sensitivity. A strong imprinting relaxation (percentage of paternal Gsα expression ≥7.5%) was found only in gsp ‐ tumors. The loss of Gsα 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 Gsα mRNA level decreased with exon 1A level, and consequently the loss of Gsα imprinting did not induce the expected Gsα overexpression. Finally, XLαs mRNA level correlated with that of paternal Gsα and of NESP55 showing the complexity of gene regulation in the GNAS locus. © 2007 Wiley‐Liss, Inc.