Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations.

Abstract

The molecular pathology of somatotrophinomas has been investigated by a combined search for dominant mutations of the gene encoding the Gsa protein and for recessive mutations involving chromosome 11q13, which contains the gene causing multiple endocrine neoplasia type I (MENI ). Somatotrophinomas and peripheral leukocytes were obtained from thirteen patients with acromegaly; one patient also suffered from MENi. Five DNA probes identifying restriction fragment length polymorphisms from 1 Iq revealed allele loss in pituitary tumors from five (four non-MENI and one MEN1) patients. Deletion mapping revealed that the region of allele loss common to the somatotrophinomas involved 1 1q13. An analysis for similar allelic deletions at 12 other loci from chromosomes 1-5, 7-9, 12-14, and 17 did not reveal generalized allele loss in the somatotrophinomas. These results, which represent the first report of chromosome 11 allele loss occurring in non-MEN1 somatotrophinomas, indicate that a recessive oncogene on 11q13 is specifically involved in the monoclonal development of somatotrophinomas. In addition Gsa mutations were detected in two non-MENi somatotrophinomas, one of which also revealed allele loss of chromosome 11. Thus, our results reveal that the development of somatotrophinomas is associated with alterations in both dominant and recessive oncogenes and further characterization of these genetic abnormalities will help to elucidate the multistep etiology and progression of somatotrophinomas. (J. Clin. Invest. 1993. 2815-2821

Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours

“…Previous studies by our own and other groups have described 11q13 LOH in sporadic (Bystrom et al, 1990;Boggild et al, 1994;Thakker et al, 1993;Bates et al, 1997;Zhuang et al, 1997b) and MEN1-associated pituitary adenomas . In addition to pituitary tumours other sporadic endocrine tumours not associated with MEN1 show variable, often frequent, LOH (3-78%) on 11q13 (Friedman et al, 1992;Lida et al, 1995;Jakobovitz et al, 1996;Debelenko et al, 1997).…”

“…Tumour subtype and grade are shown in Table 1 and have been previously investigated by us in several recent reports (Boggild et al, 1994;Thakker et al, 1993;Bates et al, 1997;Farrell et al, 1997b). Tumours were initially selected on the basis of LOH at the polymorphic marker PYGM, located centromeric and within 50 kb of the MEN1 gene (European Consortium on MEN1, 1997b).…”

“…Tumour number, subtype and radiological grade are shown in Table 1. Prior to the studies detailed below, all tumours and matched patient blood DNA were reassessed with the microsatellite marker PYGM to confirm our previous findings (Boggild et al, 1994;Thakker et al, 1993;Bates et al, 1997) of LOH at this marker. Confirmation of LOH at this marker formed the basis of the initial selection criteria for inclusion in the study.…”

“…In addition to familial tumours, recent studies have described presumed inactivating somatic mutations in several different sporadic tumour types, including parathyroid tumours , gastrinomas and insulinomas (Zhuang et al, 1997a) and in two of four pituitary tumours (Zhuang et al, 1997b) with evidence of loss of heterozygosity (LOH) within the critically deleted region on 11q13. Since we and others (Bystrom et al, 1990;Thakker et al, 1993;Boggild et al, 1994;Bates et al, 1997) have shown that a significant proportion of sporadic pituitary tumours harbour deletions (8-40%; reviewed by Thakker, 1996) that map to the critically deleted region of the MEN1 gene, we tested the hypothesis that inactivating mutations would be found on the retained allele in these tumours. We therefore carried out complete sequence analysis of all coding exons of the MEN1 gene in 23 sporadic pituitary tumours, of various subtypes, showing LOH on 11q13.…”

Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1)

“…This will have implications for the appropriate clinical and genetic management of patients and their relatives. In order to determine the frequency of phenocopy occurrence and its clinical implications, we have investigated previously reported cohorts of families [Thakker et al, 1993;Trump et al, 1996;Lemmens et al, 1997;Bassett et al, 1998;Turner et al, 2002;Lemos et al, 2007] with Multiple Endocrine Neoplasia Type 1 (MEN1), which is an autosomal dominant disorder with a high penetrance, such that >95% of patients develop endocrine tumours and clinical manifestations by the fifth decade [Thakker et al, 1989;Bassett et al, 1998;Brandi et al, 2001;Marx, 2005;Arnold and Marx, 2008]. MEN1 is characterised by the combined occurrence of tumours of the parathyroids, pancreatic islets and anterior pituitary.…”