title: Somatic mutation of the MEN1 gene in parathyroid tumours.
abstract: 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 monoclonal, 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 gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. 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 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.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: C
authors.initials: C
authors.lastname: Heppner
authors.forename: M B
authors.initials: MB
authors.lastname: Kester
authors.forename: S K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: L V
authors.initials: LV
authors.lastname: Debelenko
authors.forename: M R
authors.initials: MR
authors.lastname: Emmert-Buck
authors.forename: S C
authors.initials: SC
authors.lastname: Guru
authors.forename: P
authors.initials: P
authors.lastname: Manickam
authors.forename: S E
authors.initials: SE
authors.lastname: Olufemi
authors.forename: M C
authors.initials: MC
authors.lastname: Skarulis
authors.forename: J L
authors.initials: JL
authors.lastname: Doppman
authors.forename: R H
authors.initials: RH
authors.lastname: Alexander
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: S K
authors.initials: SK
authors.lastname: Saggar
authors.forename: I A
authors.initials: IA
authors.lastname: Lubensky
authors.forename: Z
authors.initials: Z
authors.lastname: Zhuang
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
authors.forename: S C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.forename: F S
authors.initials: FS
authors.lastname: Collins
authors.forename: A M
authors.initials: AM
authors.lastname: Spiegel
authors.forename: A L
authors.initials: AL
authors.lastname: Burns
authors.forename: S J
authors.initials: SJ
authors.lastname: Marx
mesh_terms: D002880:Chromosomes, Human, Pair 11; D016172:DNA Fingerprinting; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins
chemical_list: D004273:DNA, Neoplasm; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins