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PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex
  1. F Sandrini1,*,
  2. L S Kirschner1,*,
  3. T Bei1,
  4. C Farmakidis1,
  5. J Yasufuku-Takano2,
  6. K Takano2,
  7. T R Prezant3,
  8. S J Marx4,
  9. W E Farrell5,
  10. R N Clayton5,
  11. L Groussin6,
  12. J Bertherat6,
  13. C A Stratakis1
  1. 1Unit on Genetics and Endocrinology (UGEN), Developmental Endocrinology Branch (DEB), National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland, USA
  2. 2Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan
  3. 3University Children's Genetics Laboratory and Children's Hospital, Los Angeles, CA 90027, USA
  4. 4Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892, USA
  5. 5North Staffordshire Hospital, Keele University, Stoke on Trent, Staffordshire ST4 7QB, UK
  6. 6Département d'Endocrionlogie, Institut Cochin, 75014 Paris, France
  1. Correspondence to:
 Dr C A Stratakis, Unit on Genetics and Endocrinology, DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive MSC1862, Bethesda, Maryland 20892-1862, USA;

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The tumour suppressor gene encoding the cAMP dependent protein kinase A (PKA) type I-α regulatory subunit (RIα), PRKAR1A, has been mapped to chromosome 17q22-24 and is often mutated in the Carney complex (CNC),1,2 a multiple neoplasia and lentiginosis syndrome inherited in an autosomal dominant manner.3,4 The complex was first described as an association of lentigines, primary pigmented nodular adrenocortical disease (PPNAD), and a variety of endocrine and non-endocrine tumours (cardiac and breast myxomas).5–7 Growth hormone (GH) and prolactin (PRL) secretion abnormalities have been found in over two-thirds of patients with CNC8,9; in some cases, pituitary somatomammotrophic hyperplasia was also seen.8 GH producing adenomas (which also secrete small amounts of PRL) have been reported with increased frequency in patients with CNC; it was suggested that tumours in these patients develop in situ from precursor benign hyperplasia, following a sequence of genetic events not unlike the one described in other tissues.10,11

Genes implicated in cyclic nucleotide dependent signalling have long been considered likely candidates for pituitary tumorigenesis.12,13 Somatic activating mutations in the GNAS1 gene, which encodes the α subunit of the stimulatory G protein, lead to increased cAMP production and have been reported in approximately half of sporadic pituitary adenomas associated with acromegaly.14–16 In addition, methylation abnormalities of the GNAS1 gene are present in a significant number of pituitary tumours.17 Patients with McCune-Albright syndrome develop GH and PRL producing pituitary hyperplasia17,18 and their pituitary tissue harbours, as other affected tissues in these patients, somatic, activating mutations of the GNAS1 gene.19–21

In the present study, we investigated a large collection of sporadic pituitary adenomas (SPA) from the USA, UK, Japan, and France for loss of heterozygosity (LOH) of the 17q22-24 PRKAR1A …

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  • * The first two authors contributed equally to this work.