Abstract
The majority of pituitary tumours are monoclonal in origin and arise sporadically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1). Whilst a multi-step aetiology involving both oncogenes and tumour suppressor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumours have been shown to harbour allelic deletion on 11q13, which is the location of the recently cloned MEN1 gene. We investigated 23 sporadic pituitary tumours previously shown to harbour allelic deletion on 11q13 with the marker PYGM centromeric and within 50 kb of the MEN1 locus. In addition, the use of intragenic polymorphisms in exon 9 and at D11S4946, and of telomeric loci at D11S4940 and D11S4936, revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene. However, the overall pattern of loss in informative cases was indicative of non-contiguous deletion that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DNA, did not reveal mutation(s) in any of the 23 tumours studied. A benign polymorphism in exon 9 was encountered at the expected frequency, and in seven patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reaction analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that gene silencing is unlikely to be mechanistic in sporadic pituitary tumorigenesis, they do not exclude changes in the level or stability of the transcript or translation to mature protein. Our study would support and extend very recent reports of a limited role for mutations in the MEN1 gene in sporadic pituitary tumours. Alternatively, these findings may point to an, as yet, unidentified tumour suppressor gene in this region.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhengping, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S-E, Liotta, L. A., Chandrasekarappa, S. C., Collins, F. S., Spiegal, A. M., Lee Burns, A. & Marx, S. J. (1997) Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 6: 1169–1175.
Alexander, J. M., Biller, B. M. K., Bikkal, H., Zervas, N. T., Arnold, A. & Klibanski, A. (1990) Clinically non-functioning pituitary tumors are monoclonal in origin. J Clin Invest 86: 336–340.
Bassett, J. H. D., Forbes, S. A., Pannett, A. A. J., Lloyd, S. E., Christie, P. T., Wooding, C., Harding, B., Besser, G. M., Monson, J. P., Sampson, J., Wass, A. H., Wheeler, M. H. & Thakker, R. V. (1998) Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62: 232–244.
Bates, A. S., Farrell, W. E., Bicknell, E. J., Talbot, A. J., Broome, J. C., Perrett, C. W., Thakker, R. V. & Clayton, R. N. (1997) Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 82: 818–824.
Boggild, M. D., Jenkinson, S., Pistorello, M., Boscaro, M., Scanarini, M., Ternan, M. c., Perret, C. W., Thakker, R. V. & Clayton, R. N. (1994) Molecular genetic studies of sporadic pituitary tumours. J Clin Endocrinol Metab 78: 387–392.
Bystrom, C., Larsson, C., Blomberg, C., Sandelin, K., Falkmer, E., Skogseid, B., Oberg, K., Werner, S. & Nordenskjold, M. (1990) Localisation of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumours. Proc Natl Acad Sci USA 87: 1968–1972.
Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S-E, Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agerwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegal, A. M., Burns, A. L. & Marx, S. J. (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276: 404–407.
Chomczynski, P. & Sacchi, N. (1987) Single step method of RNA isolation by acid guanidine thiocyanate extraction. Anal Biochem 162: 156–159.
Clementi, E., Malgaretti, N., Meldolesi, J. & Taramelli, R. (1990) A new constitutively activating mutation in Gs protein α subunit-gsp oncogene is found in human pituitary tumours. Oncogene 5: 1059–1061.
Cryns, V., Alexander, J. M., Klibanski, A. & Arnold, A. (1993) The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab 77: 644–646.
Debelenko, L. V., Zhuang, Z., Emmert-Buck, M. R., Chandrasekharappa, S. C., Manickam, P., Guru, S. C., Marx, S. J., Skarulis, M. C., Spiegal, A. M., Collins, F. S., Jenson, R. T., Liotta, L. A. & Lubensky, I. A. (1997) Allelic deletion on chromosome 11q13 in MEN1-associated and sporadic gastrinomas and pancreatic endocrine tumours. Cancer Res 57: 2238–2243.
Dong, Q., Debelenko, L. V., Chadrasekharappa, S. C., Emmert-Buck, M. R., Zhuang, Z., Guru, S. C., Manickam, P., Skarulis, M., Lubensky, I. A., Liotta, L. A., Collins, F. S., Marx, S. J. & Spiegal, A. M. (1997) Loss of heterozygosity at 11q13: analysis of pituitary tumours, lung carcinoids, lipomas and other uncommon tumours in subjects with familial multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 82: 1416–1420.
European Consortium on, MEN1 (1997a) Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Hum Mol Genet 6: 1177–1183.
European Consortium on, MEN1 (1997b) Construction of a 1.2Mb sequence ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. Genomics 44: 94–100.
Farrell, W. E., Simpson, D. J., Bicknell, J., McNicol, A. M. & Clayton, R. N. (1997a). Methylation of the tumour supressor gene (TSG) CDKN2/MTS1 occurs frequently in invasive and non-invasive pituitary adenomas and is associated with loss of p16 expression. Mutation Detection 4th International Workshop; Human Genome Organisation, Brno Czech Republic. (abstract): 25
Farrell, W. E., Simpson, D., Bates, A. S., Talbot, J. A., Bicknell, J. & Clayton, R. N. (1997b) Chromosome 9 p deletions in invasive and non invasive non-functional pitutary adenomas: The deleted region involves markers outside of the MTS1 and MTS2 gene. Cancer Res 57: 2703–2709.
Friedman, E., DE Marco, L., Gejman, P. V., Norton, J. A., Bale, A. E., Aurbach, G. D., Spiegal, A. M. & Marx, S. J. (1992) Allelic loss from chromosome 11 in parathyroid tumours. Cancer Res 52: 6804–6809.
Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., EmmertBuck, M. R., Guru, S. C., Manickam, P., Olufemi, S. E., Skarulis, M. C., Doppman, J. L., Alender, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z. P., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L. & Marx, S. J. (1997) Somatic mutations of the MEN1 gene in parathyroid tumours. Nature Gen 16: 375–378.
Herman, V., Fagin, J., Gonsky, R., Kovaks, K. & Melmed, S. (1990) Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71: 1427–1433.
Jakobovitz, O., Nass, D., DeMarco, L., Barbosa, A. J. A., Simoni, F. B. & Rechavi, G. Friedman (1996) Carcinoid tumours frequently display genetic abnormalities involving chromosome 11. J Clin Endocrinol Metab 81: 3164–3167.
Landis, C. A., Masters, S. B., Spada, A., Pace, A. M., Bourne, H. R. & Vallar, L. (1989) GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenyl cyclase in human pituitary tumours. Nature 340: 692–696.
Lida, A., Blake, K., Tunny, T., Klemm, S., Stowasser, M., Hayward, N., Gordon, R., Nakamura, Y. & Imai, T. (1995) Allelic losses on chromosome band 11q13 in aldosterone-producing adrenal tumours. Genes Chromosomes Cancer 12: 73–75.
Lyons, J., Landis, C. A., Harsh, G., Harsh, G., Vallar, L., Grunewald, K., Feichtinger, H., Duh, Q. Y., Clarke, O. H., Kawasaki, E. & Bourne, H. R. McCormick (1990) Two G protein oncogenes in human endocrine tumours. Science 249: 655–659.
Manickam, P., Guru, S. C., Debelenko, L. V., Agarwal, S. K., Olufemi, S-E, Weisemann, J. M., Boguski, M. S., Crabtree, J. S., Wang, Y. P., Roe, B. A., Lubensky, I. A., Zhuang, Z. P., Kester, M. B., Burns, A. L., Spiegel, A. M., Marx, S. J., Liotta, L. A., EmmertBuck, M. R., Collins, F. S. & Chandrasekharappa, S. C. (1997) Eighteen new polymorphic markers in the multiple endocrine neoplasia type 1 (MEN1) region. Hum Genet 101: 102–108.
Melmed, S. (1994). Pituitary neoplasia. In: Multiple Endocrine Neoplasia, Gagel RF (ed). Endocrinol Metab Clinics North Am 23: 81–92
Pei, L., Melmed, S., Scheithauer, B., Kovaks, K., Benedict, W. E. & Prager, D. (1995) Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors: evidence for a chromosome 13 tumour supressor gene other than RB. Cancer Res 55: 644–646.
Pei, L. & Melmed, S. (1996) Oncogenes and tumour suppressor genes in pituitary tumorigenesis. In Oncogenesis and Molecular Biology of Pituitary Tumours, Melmed S (ed). Front Horm Res 20: 122–136.
Prezant, T. R., Levine, J. & Melmed, S. (1998). Molecular characterization of the MEN1 tumour suppressor gene in sporadic pituitary tumors. J Clin Endocrinol Metab(in press)
Simpson, D. J., Bicknell, J. E., McNicol, A. M., Clayton, R. N. & Farrell, W. E. (1999) Hypermethylation of the p16/CDKN2A/MTS1 gene and loss of protein expression is associated with non-functional pituitary adenomas but not somatotrophinomas. Genes, Chromosomes Cancer 24: 328–336.
Shimon, I. & Melmed, S. (1997) Genetic basis of endocrine disease: pituitary tumor pathogeneis. J Clin Endocrinol Metab 82: 1675–1681.
Sumi, T., Stefaneanu, L., Kovaks, K., Asa, S. & Rindi, G. (1993) Immunohistochemical study of p53 protein in human and animal pituitary tumours. Endocrinol Pathol 4: 95–99.
Thakker, R. V. (1993) The molecular genetics of the multiple endocrine neoplasia syndrome. Clin Endocrinol 38: 1–14.
Thakker, R. V. (1996) Role of chromosome 11 in hereditary and sporadic pituitary tumourigenesis. In. Front Hormone Research, Melmed S (ed). Basel, Karger 20: 179–193.
Thakker, R. V., Pook, M. A., Wooding, C., Boscaro, M., Scanarini, M. & Clayton, R. N. (1993) Association of somatotrophinomas with loss of alleles on chromosome 11 with gsp mutations. J Clin Invest 91: 2815–2821.
Woloschak, M., Yu, A., Xiao, J. & Post, K. D. (1996) Frequent loss of the p16INK4a gene product in human pituitary tumours. Cancer Res 56: 2493–2486.
Woloschak, M., Yu, A. & Post, K. D. (1997) Frequent inactivation of the p16 gene in human pituitary tumours by gene methylation. Mol Carcinogen 19: 221–224.
Zhu, J., Leon, S. P., Beggs, A. H., Busque, L., Gilliland, D. G. & Black, P. M. (1994) Human pituitary adenomas show no loss of herozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab 78: 922–927.
Zhuang, Z. P., Vortmeyer, A. O., Pack, S., Huang, S., Pham, T. A., Wang, C. Y., Park, W. S., Agarwal, S. K., Debelenko, L. V., Kester, M., Guru, S. C., Manickam, P., Olufemi, S. E., Yu, F., Heppner, C., Crabtree, J. S., Skarulis, M. C., Venzon, D. J., EmmertBuck, M. R., Spiegel, A. M., Chandrasekhrapper, S. C., Collins, F. S., Burns, A. L., Marx, S. J., Jensen, R. T. & Liotta, L. A. Lubensky (1997a) Somatic mutations of the MEN1 tumour suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 57: 4682–4686.
Zhuang, Z., Ezzat, S. Z., Vortmeyer, A. O., Weil, R., Oldfield, E. H., Park, S. P., Pack, S., Huang, S., Agarwal, S. K., Guru, S. C., Manickam, P., Debelenko, L. V., Kester, M. B., Olufemi, S. E., Heppner, C., Crabtree, J. S., Burns, A. L., Spiegel, A. M., Marx, S. J., Chandrasekharappa, S. C., Collins, F. S., Emmert-Buck, M. R., Liotta, L. A., Asa, S. L. & Lubensky IA Walker LM Holm A Oberg A Sundqvist T El Haj, A. J. (1997b) Mutation of the MEN1 tumour suppressor gene in pituitary tumours. Cancer Res 57: 5446–5451.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Farrell, W., Simpson, D., Bicknell, J. et al. Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours. Br J Cancer 80, 44–50 (1999). https://doi.org/10.1038/sj.bjc.6690319
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690319
Keywords
This article is cited by
-
Sporadic pituitary adenoma with somatic double-hit loss of MEN1
Pituitary (2023)
-
Genetic mutations in sporadic pituitary adenomas—what to screen for?
Nature Reviews Endocrinology (2015)
-
MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas
Pituitary (2011)
-
The molecular biology of pituitary tumors: a personal perspective
Pituitary (2009)
-
Molecular pathogenesis of human prolactinomas identified by gene expression profiling, RT-qPCR, and proteomic analyses
Pituitary (2008)