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Association of Somatotrophinomas with Loss of Alleles on Chromosome 11 and with Gsp Mutations

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Association of Somatotrophinomas with Loss of Alleles on Chromosome 11 and with Gsp Mutations Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. R V Thakker, … , M Scanarini, R N Clayton J Clin Invest. 1993;91(6):2815-2821. https://doi.org/10.1172/JCI116524. Research Article The molecular pathology of somatotrophinomas has been investigated by a combined search for dominant mutations of the gene encoding the Gs alpha protein and for recessive mutations involving chromosome 11q13, which contains the gene causing multiple endocrine neoplasia type 1 (MEN1). Somatotrophinomas and peripheral leukocytes were obtained from thirteen patients with acromegaly; one patient also suffered from MEN1. Five DNA probes identifying restriction fragment length polymorphisms from 11q revealed allele loss in pituitary tumors from five (four non-MEN1 and one MEN1) patients. Deletion mapping revealed that the region of allele loss common to the somatotrophinomas involved 11q13. 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 Gs alpha mutations were detected in two non-MEN1 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. Find the latest version: https://jci.me/116524/pdf Association of Somatotrophinomas with Loss of Alleles on Chromosome 1 1 and with gsp Mutations R. V. Thakker,* M. A. Pook,* C. Wooding,* M. Boscaro, M. Scanarini,t and R. N. Clayton5 *M.R.C Molecular Medicine Group, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, United Kingdom; *Department of Endocrinology & Neurosurgery, University ofPadua, Italy; §Department ofEndocrinology & Diabetes Mellitus, North Staffordshire Royal Infirmary, Stoke-on-Trent, United Kingdom Abstract of somatotrophinomas, which are growth hormone (GH)-se- creting pituitary tumors (4, 5). This Gs protein a chain muta- The molecular pathology of somatotrophinomas has been in- tion, which is also referred to as a gsp mutation, was found in vestigated by a combined search for dominant mutations of the 40% of somatotrophinomas (5). In the remaining 60% of so- gene encoding the Gsa protein and for recessive mutations in- matotrophinomas abnormalities in other genes are likely to be volving chromosome 11q13, which contains the gene causing involved. Somatotrophinomas are known to occur in families multiple endocrine neoplasia type I (MENI ). Somatotrophino- either as an isolated autosomal dominant endocrinopathy (6, mas and peripheral leukocytes were obtained from thirteen pa- 7), or as part of the autosomal dominant Multiple Endocrine tients with acromegaly; one patient also suffered from MENi. Neoplasia Type 1 (MEN 1 )' syndrome (8), which is character- Five DNA probes identifying restriction fragment length poly- ized by the combined occurrence of tumors of the parathy- morphisms from 1 Iq revealed allele loss in pituitary tumors roids, the pancreatic islets, and pituitary. The occurrence of from five (four non-MENI and one MEN1) patients. Deletion such inherited somatotrophinomas suggests that recessively mapping revealed that the region of allele loss common to the acting tumor suppressor genes, which are particularly involved somatotrophinomas involved 1 1q13. An analysis for similar al- in hereditary neoplasms such as retinoblastoma (3), may be lelic deletions at 12 other loci from chromosomes 1-5, 7-9, associated with the etiology of some tumors. In order to local- 12-14, and 17 did not reveal generalized allele loss in the soma- ize and establish the role of such tumor suppressor genes in the totrophinomas. These results, which represent the first report development of a tumor (9, 10), a demonstration of a loss of of chromosome 11 allele loss occurring in non-MEN1 somato- tumor heterozygosity, revealed by a comparison of leukocyte trophinomas, indicate that a recessive oncogene on 11q13 is and tumor alleles, is required. The tumor suppressor gene caus- specifically involved in the monoclonal development of somato- ing MEN 1 has been localized to the pericentromeric region of trophinomas. In addition Gsa mutations were detected in two the long arm of chromosome 11 ( 1 q13) (11, 12), but a pre- non-MENi somatotrophinomas, one of which also revealed al- vious study of 10 somatotrophinomas (9 non-MEN 1 and 1 lele loss of chromosome 11. Thus, our results reveal that the MEN 1) did not detect allelic deletions involving chromosome development of somatotrophinomas is associated with alter- 11 ( 13). This finding contrasts with the observed chromosome ations in both dominant and recessive oncogenes and further 11 allele loss in sporadic non-MEN 1 and MENI parathyroid characterization of these genetic abnormalities will help to elu- tumors ( 12-14), and it has been proposed that sporadic pitu- cidate the multistep etiology and progression of somatotrophi- itary tumors may not arise through inactivation of the MEN 1 nomas. (J. Clin. Invest. 1993. 2815-2821.) Key words: tumor gene ( 15). In order to investigate this further, we have per- suppressor genes * tumorigenesis * acromegaly formed detailed deletion mapping studies using 14 DNA probes from chromosome 11. Our results indicate that a reces- Introduction sive tumor suppressor oncogene in the 1 q 13 region is in- volved in the monoclonal development ofsporadic non-MEN 1 The development of tumors may be associated with an activa- and MEN 1 somatotrophinomas. Thus, somatotrophinomas tion of dominant oncogenes or an inactivation of recessive on- may arise through activation of dominant oncogenes (4, 5) or cogenes ( 1, 2), which are also referred to as anti-oncogenes or through inactivation of recessive tumor suppressor oncogenes. tumor suppressor genes (3). A dominantly acting oncogene, due to a point mutation in one copy of the gene encoding the a Methods chain of the guanine nucleotide (GTP) binding subunit of the stimulatory regulator of adenylyl cyclase, referred to as the Gs Clinical material. Pituitary tumors and peripheral blood samples were protein, has been demonstrated to be associated with a subset collected from 13 acromegalic patients (6 males and 7 females) with an age range of 20 to 65 yr (Table I). Patients 1 to 11 had no clinical history for the other endocrine tumors of the MEN1 syndrome, and Address correspondence to Dr. R. V. Thakker, MRC Molecular Medi- biochemical investigations revealed normocalcemia and normal circu- cine Group, Collier Building, Royal Postgraduate Medical School, lating concentrations of parathyroid hormone. In addition, clinical his- Hammersmith Hospital, Du Cane Road, London W12 ONN, United tory revealed no evidence for inherited MEN 1 tumors among the first- Kingdom. degree relatives. Patient 12, who had previously been treated for Receivedfor publication 12 December 1991 and in revisedform 19 Conn's syndrome by a unilateral adrenalectomy, suffered from a nodu- January 1993. lar goiter and insulin-dependent diabetes mellitus; this patient's endo- J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 1. Abbreviations used in this paper: MEN 1, multiple endocrine neopla- 0021-9738/93/06/2815/07 $2.00 sia type 1; PGA, pepsinogen; PYGM, phosphorylase glycogen muscle, Volume 91, June 1993, 2815-2821 McArdle syndrome; WT, wild type sequence. Allelic Deletions in Somatotrophinomas 2815 crine tumors were not typical of MEN 1 and this patient was classified utilized to correct for differences in the amount of DNA in each lane: I,, in the non-MEN 1 group. Patient 13 had primary hyperparathyroidism = IT ('XL/IXT), where IT denotes the intensity of the tumor allele and a family history of MEN 1. Additional clinical, biochemical, histo- relative to the corresponding leukocyte allele obtained with a probe logical, and immunocytochemistry findings for each patient are shown from chromosome 11, and IXL and IXT denote the intensities obtained in Table I. The pituitary tumor tissue was obtained at the time of with the X chromosome probe from the leukocyte and tumor DNA, surgery and stored at -70°C and the venous blood samples were col- respectively. A ratio of less than 1.5 in the relative intensity of the lected in tubes containing EDTA (0.5M pH 8.0) and kept frozen retained tumor allele to the intensity of the corresponding leukocyte at -700C. allele (IrT/IL) was indicative of tumor DNA hemizygosity, whereas a DNA hybridization analysis. DNA from leukocytes and tumors ratio exceeding 1.9 was indicative of tumor homozygosity. was prepared by standard methods (16, 17). Leukocyte DNA samples Tumor-associated allelic deletions involving other autosomes were were first assessed at each ofthe 14 loci on chromosome 11 (Fig. 1 ) and assessed by utilizing the 20 DNA probes DIS7, D2S44, D3S44, tumor DNA analysis was performed only at loci which revealed leuko- D4S125, D5S43, D6S44, D7S21, D8S17, D9S7, D1OS28, D12Sll, cyte heterozygosity. 8 Mg of DNA was digested to completion with a D13S37, D14S13, D15S38, D16S137, D17S24, D18S22, D19S20, fourfold excess of one of the following restriction
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