Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma

被引:381
作者
Shattuck, TM
Välimäki, S
Obara, T
Gaz, RD
Clark, OH
Shoback, D
Wierman, ME
Tojo, K
Robbins, CM
Carpten, JD
Farnebo, LO
Larsson, C
Arnold, A
机构
[1] Univ Connecticut, Sch Med, Ctr Mol Med, Farmington, CT 06030 USA
[2] Univ Connecticut, Sch Med, Div Endocrinol & Metab, Farmington, CT 06030 USA
[3] Karolinska Hosp, Dept Mol Med, S-10401 Stockholm, Sweden
[4] Karolinska Hosp, Dept Surg Sci, S-10401 Stockholm, Sweden
[5] Tokyo Womens Med Univ, Dept Endocrine Surg, Sinjuku Ku, Tokyo, Japan
[6] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
[7] Univ Calif San Francisco, Mt Zion Med Ctr, Dept Surg, San Francisco, CA 94143 USA
[8] Univ Calif San Francisco, Vet Affairs Med Ctr, Endocrine Res Unit, San Francisco, CA 94143 USA
[9] Univ Colorado, Vet Affairs Med Ctr, Div Endocrinol, Denver, CO 80202 USA
[10] Jikei Univ, Sch Med, Dept Internal Med, Div Diabet & Endocrinol, Tokyo, Japan
[11] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1056/NEJMoa031237
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND: We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, in sporadic parathyroid carcinoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism -- hyperparathyroidism-jaw tumor (HPT-JT) syndrome -- that carries an increased risk of parathyroid cancer. METHODS: We directly sequenced the full coding and flanking splice-junctional regions of the HRPT2 gene in 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism or the HPT-JT syndrome at presentation. We also sought to confirm the somatic nature of the identified mutations and tested the carcinomas for tumor-specific loss of heterozygosity at HRPT2. RESULTS: Parathyroid carcinomas from 10 of the 15 patients had HRPT2 mutations, all of which were predicted to inactivate the encoded parafibromin protein. Two distinct HRPT2 mutations were found in tumors from five patients, and biallelic inactivation as a result of a mutation and loss of heterozygosity was found in one tumor. At least one HRPT2 mutation was demonstrably somatic in carcinomas from six patients. Unexpectedly, HRPT2 mutations in the parathyroid carcinomas of three patients were identified as germ-line mutations. CONCLUSIONS: Sporadic parathyroid carcinomas frequently have HRPT2 mutations that are likely to be of pathogenetic importance. Certain patients with apparently sporadic parathyroid carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant.
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页码:1722 / 1729
页数:8
相关论文
共 35 条
[31]  
SZABO J, 1995, AM J HUM GENET, V56, P944
[32]   Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: Linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas [J].
Teh, BT ;
Farnebo, F ;
Kristoffersson, U ;
Sundelin, B ;
Cardinal, J ;
Axelson, R ;
Yap, A ;
Epstein, M ;
Heath, H ;
Cameron, D ;
Larsson, C .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (12) :4204-4211
[33]  
VETTO JT, 1993, SURGERY, V114, P882
[34]   NATURAL-HISTORY OF PARATHYROID CARCINOMA - DIAGNOSIS, TREATMENT, AND RESULTS [J].
WANG, CA ;
GAZ, RD .
AMERICAN JOURNAL OF SURGERY, 1985, 149 (04) :522-527
[35]   Genetic studies of a family with hereditary hyperparathyroidism jaw tumour syndrome [J].
Wassif, WS ;
Farnebo, F ;
Teh, BT ;
Moniz, CF ;
Li, FY ;
Harrison, JD ;
Peters, TJ ;
Larsson, C ;
Harris, P .
CLINICAL ENDOCRINOLOGY, 1999, 50 (02) :191-196