Nature Genetics
16, 375 - 378 (1997)
doi:10.1038/ng0897-375
Somatic mutation of the MEN1 gene in parathyroid tumoursChristina Heppner1, *, Mary Beth Kester1, *, Sunita K. Agarwal1, *, Larisa V. Debelenko2, Michael R. Emmert-Buck2, Siradanahalli C. Guru3, Pachiappan Manickam3, Shodimu-Emmanuel Olufemi3, Monica C. Skarulis1, John L. Doppman4, Richard H. Alexander5, Young S. Kim1, Suraj K. Saggar1, Irina A. Lubensky2, Zhengping Zhuang2, Lance A. Liotta2, Settara C. Chandrasekharappa3, Francis S. Collins3, Alien M. Spiegel1, A. Lee Burns1
& Stephen J. Marx1, 6
1Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
2Laboratory of Pathology, National Cancer Institute, NIH
3Laboratory of Gene Transfer, National Human Genome Research Institute, NIH
4Diagnostic Radiology Department, Clinical Center, NIH
5Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
*C.H., M.B.K. and S.K.A. contributed equally to this work.
6e-mail: stephenm@amb.niddk.nih.gov Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal3,4, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene4−8. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene9. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.
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