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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

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Abstract

Although the molecular mechanisms underlying GH secreting pituitary tumor formation are not well understood, mutations in the α-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.

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Acknowledgments

Funded by grants from the National Institutes of Health, DK02561, DK 073040 and DK064720 (to PUF), RR-00645 to the Columbia University GCRC and the Herbert Irving Clinical Scholars Program (to WKC). The authors wish to thank Mr. Robert Sundeen for expert technical assistance with growth hormone and IGF-I measurements. Presented in part at the 88th Annual Meeting of The Endocrine Society, June 2006.

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Authors and Affiliations

  1. Department of Medicine, Columbia University College of Physicians & Surgeons, 650 West 168th Street, 9-905, New York, NY, USA

    Pamela U. Freda & M. Nabi Kanibir

  2. Department of Pediatrics, Columbia University College of Physicians & Surgeons, New York, NY, USA

    Wendy K. Chung & Naoki Matsuoka

  3. Department of Neurosurgery, Mt. Sinai Medical Center, New York, NY, USA

    Jane E. Walsh & Kalmon D. Post

  4. Department of Pathology, Mt. Sinai Medical Center, New York, NY, USA

    George Kleinman

  5. Department of Statistics, Columbia University College of Physicians & Surgeons, New York, NY, USA

    Yuanjia Wang

  6. Department of Neurosurgery, Columbia University College of Physicians & Surgeons, New York, NY, USA

    Jeffrey N. Bruce

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  1. Pamela U. Freda
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Correspondence to Pamela U. Freda.

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Freda, P.U., Chung, W.K., Matsuoka, N. et al. 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. Pituitary 10, 275–282 (2007). https://doi.org/10.1007/s11102-007-0058-2

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  • DOI: https://doi.org/10.1007/s11102-007-0058-2

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