{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:37:02Z","timestamp":1791286622886,"version":"4.1.0"},"reference-count":26,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,9,1]]},"abstract":"<jats:p>MEN type 1 is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroids, anterior pituitary, and pancreatic islet cells. The MEN1 gene, which is located on chromosome 11q13, consists of 10 exons and encodes a 610-amino acid protein named MENIN. The observation of LOH involving 11q13 in MEN type 1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the \u201ctwo-hit\u201d model of hereditary cancer. The second hit in MEN type 1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur, and the other mechanisms, such as intragenic deletions or point mutations that inactivate the gene, have not been reported in MEN type 1 tumors. We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically. This revealed four somatic mutations, which consisted of two missense mutations and two frameshift mutations in two parathyroid tumors, one insulinoma, and one lipoma. Thus, our results, which represent the first small intragenic somatic mutations reported in MEN type 1 tumors, provide further evidence that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by Knudson\u2019s \u201ctwo-hit\u201d hypothesis.<\/jats:p>","DOI":"10.1210\/jcem.86.9.7844","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:07:29Z","timestamp":1389200849000},"page":"4371-4374","source":"Crossref","is-referenced-by-count":14,"title":["Somatic Mutations in MEN Type 1 Tumors, Consistent with the Knudson \u201cTwo-Hit\u201d Hypothesis"],"prefix":"10.1210","volume":"86","author":[{"given":"Anna A. J.","family":"Pannett","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Group, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh V.","family":"Thakker","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Group, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071617384786600_R1","first-page":"489","article-title":"Multiple endocrine neoplasia type 1","author":"Marx","year":"1998","journal-title":"In: Vogelstein B, Kinzler KW, eds. The genetic basis of human cancer. New York: McGraw-Hill;"},{"key":"2020071617384786600_R2","first-page":"2815","article-title":"Multiple endocrine neoplasia type 1","author":"Thakker","year":"1995","journal-title":"In: DeGroot LJ, ed. Endocrinology, 3rd Ed. Philadelphia: W.B. Saunders;"},{"key":"2020071617384786600_R3","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1073\/pnas.95.4.1630","article-title":"Menin, the product of the MEN1 gene, is a nuclear protein.","volume":"95","author":"Guru","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617384786600_R4","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1126\/science.276.5311.404","article-title":"Positional cloning of the gene for multiple endocrine neoplasia-type 1.","volume":"276","author":"Chandrasekharappa","year":"1997","journal-title":"Science"},{"key":"2020071617384786600_R5","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/hmg\/6.7.1177","article-title":"Identification of the multiple endocrine neoplasia type 1 (MEN1) gene.","volume":"6","year":"1997","journal-title":"Hum Mol Genet"},{"key":"2020071617384786600_R6","first-page":"730","article-title":"Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.","volume":"84","author":"Agarwal","year":"1999","journal-title":"Cell"},{"key":"2020071617384786600_R7","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/hmg\/6.7.1169","article-title":"Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.","volume":"6","author":"Agarwal","year":"1997","journal-title":"Hum Mol Genet"},{"key":"2020071617384786600_R8","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1086\/301729","article-title":"Characterization of mutations in patients with multiple endocrine neoplasia type 1.","volume":"62","author":"Bassett","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2020071617384786600_R9","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1086\/302097","article-title":"A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors.","volume":"63","author":"Teh","year":"1998","journal-title":"Am J Hum Genet"},{"key":"2020071617384786600_R10","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1677\/erc.0.0060449","article-title":"Multiple endocrine neoplasia type 1.","volume":"6","author":"Pannett","year":"1999","journal-title":"Endocr Relat Cancer"},{"key":"2020071617384786600_R11","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and cancer: statistical study of retinoblastoma.","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617384786600_R12","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/ng0897-375","article-title":"Somatic mutation of the MEN1 gene in parathyroid tumours.","volume":"16","author":"Heppner","year":"1997","journal-title":"Nat Genet"},{"key":"2020071617384786600_R13","first-page":"4682","article-title":"Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas.","volume":"57","author":"Zhuang","year":"1997","journal-title":"Cancer Research"},{"key":"2020071617384786600_R14","first-page":"377","article-title":"Mutation of the multiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas.","volume":"58","author":"Hessman","year":"1998","journal-title":"Cancer Res"},{"key":"2020071617384786600_R15","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1093\/hmg\/6.13.2285","article-title":"Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung.","volume":"6","author":"Debelenko","year":"1997","journal-title":"Hum Mol Genet"},{"key":"2020071617384786600_R16","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/332085a0","article-title":"Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.","volume":"332","author":"Larsson","year":"1988","journal-title":"Nature"},{"key":"2020071617384786600_R17","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1056\/NEJM198907273210403","article-title":"Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11.","volume":"321","author":"Thakker","year":"1989","journal-title":"N Engl J Med"},{"key":"2020071617384786600_R18","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJM198907273210402","article-title":"Clonality of parathyroid tumours in familial multiple endocrine neoplasia type 1.","volume":"321","author":"Friedman","year":"1989","journal-title":"N Engl J Med"},{"key":"2020071617384786600_R19","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1136\/jmg.34.8.617","article-title":"Localisation of a gene causing endocrine neoplasia to a 4 cM region on chromosome 1p35\u2013p36.","volume":"34","author":"Williamson","year":"1997","journal-title":"J Med Genet"},{"key":"2020071617384786600_R20","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1006\/geno.1996.0570","article-title":"Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13.","volume":"37","year":"1996","journal-title":"Genomics"},{"key":"2020071617384786600_R21","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/(SICI)1098-2264(199806)22:2<130::AID-GCC7>3.0.CO;2-Y","article-title":"Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13.","volume":"22","author":"Chakrabarti","year":"1998","journal-title":"Genes Chromosomes Cancer"},{"key":"2020071617384786600_R22","doi-asserted-by":"crossref","first-page":"7351","DOI":"10.1073\/pnas.90.15.7351","article-title":"Molecular mechanisms of oncogenic muations in tumours from patients with bilateral and unilateral retinoblastoma.","volume":"90","author":"Hogg","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617384786600_R23","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1172\/JCI9462","article-title":"Epigenetic gene silencing in cancer.","volume":"105","author":"Tycko","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071617384786600_R24","doi-asserted-by":"crossref","first-page":"9700","DOI":"10.1073\/pnas.91.21.9700","article-title":"Silencing of the VHL tumor- suppressor gene by DNA methylation in renal carcinoma.","volume":"91","author":"Herman","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617384786600_R25","first-page":"765","volume":"60","author":"Prowse","journal-title":"Am J Hum Genet"},{"key":"2020071617384786600_R26","doi-asserted-by":"crossref","first-page":"6870","DOI":"10.1073\/pnas.95.12.6870","article-title":"Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.","volume":"95","author":"Herman","year":"1998","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/86\/9\/4371\/9168038\/jcem4371.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/86\/9\/4371\/9168038\/jcem4371.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T03:35:02Z","timestamp":1594956902000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/86\/9\/4371\/2848973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,9,1]]},"references-count":26,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2001,9,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jcem.86.9.7844","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,9,1]]}}}