Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission

Abstract

Although the molecular mechanisms underlying GH secreting pituitary tumor formation are not well understood, mutations in the alpha-subunit of the stimulatory G gene, GNAS, have been identified in up to 40%. As these mutations could play a role in tumor growth, we screened 60 GH secreting tumors for GNAS mutations and assessed whether mutation status correlated with their clinical and pathological characteristics. Tumor specimens obtained at surgery were snap frozen. Tumor DNA was extracted, and PCR was used to amplify regions containing 2 sites of recurrent activating somatic mutations in codons 201 and 227 in GNAS. Amplicons were bi-directionally sequenced and analyzed. GNAS mutations were present in 24/60 (40%) of tumors; these were arg201cys(n = 15), arg201ser(n = 2), arg201his(n = 2), gln227leu(n = 4), gln227arg(n = 1). Preoperative IGF-I levels (age-adjusted) were higher (p = 0.01), but GH levels were slightly higher (p = 0.18) in mutation positive vs. negative groups. Mutation positive tumors were somewhat smaller than negative tumors (p = 0.07). The proportion of tumors >2 cm was somewhat less among positive (8.3%) vs. negative tumors (25%) (p = 0.10). Neither mib proliferation index, the proportion of invasive tumors nor surgical remission rates differed in the groups. IGF-I normalization rate with somatostatin analog therapy was similar in positive (3 of 6) vs. negative (3 of 7) patients. GH secreting tumors harboring GNAS mutations had higher preoperative IGF-I levels, somewhat higher preoperative GH levels and tended to be smaller than tumors without mutations. Presence of a GNAS mutation did not predict a difference in a proliferation marker, surgical remission or response to somatostatin analog therapy.

GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

“…[32][33][34] Approximately 40% of pituitary somatotroph (growth hormone secreting) adenomas demonstrate GNAS mutations at either codon 201 or codon 227. 35 GNAS mutations are uncommon in epithelial malignancies, occurring only in minor subsets of colorectal, prostate and breast cancers, renal cell carcinomas and small cell carcinomas of the lung, and these mutations are almost always restricted to codon 201. [36][37][38][39][40] In the hepatobiliary region, GNAS mutations have been reported in only two of 245 (~1%) hepatocellular carcinomas (HCCs) and in four of 164 (2.4%) hepatocellular adenomas.…”

“…Another caveat may be that the activating hotspot mutation in IPNBs is not at GNAS codon 201, but, rather, at codon 227, which was not examined in the current study. However, based on the data that GNAS mutations in epithelial neoplasms (including IPMNs) are always restricted to codon 201, 9,35,42 the authors find this possibility unlikely. Finally, the issue of assay sensitivity, which is always a concern in a 'negative' study of this nature, should be addressed.…”

SAGE analysis highlights the putative role of underexpression of ribosomal proteins in GH-secreting pituitary adenomas

“…Primers and PCR conditions to detect activating mutations of GNAS gene (gsp oncogene) and AIP mutations in tumoral DNA were previously described (7,16).…”

Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma

“…Approximately 40% of patients with sporadic acromegaly harbor somatic GNAS mutations, leading to constitutively activated cAMP pathway [6]. In general, somatotropinoma harboring GNAS mutations tended to have higher serum GH and IGF-I levels, smaller tumor, and good response to somatostatin analogues (SSA) and dopamine agonists (DA) [7,8].…”