FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 349:1722-1729 October 30, 2003 Number 18 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Weinstein, L. S. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

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.

Source Information

From the Center for Molecular Medicine (T.M.S., A.A.) and the Division of Endocrinology and Metabolism (A.A.), University of Connecticut School of Medicine, Farmington; the Departments of Molecular Medicine (S.V., C.L.) and Surgical Sciences (S.V., L.-O.F.), Karolinska Hospital, Stockholm, Sweden; the Department of Endocrine Surgery, Tokyo Women's Medical University, Sinjuku-ku, Tokyo, Japan (T.O.); the Department of Surgery, Massachusetts General Hospital, Boston (R.D.G.); the Department of Surgery, University of California, San Francisco, Mt. Zion Medical Center, San Francisco (O.H.C.); the Endocrine Research Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco (D.S.); the Division of Endocrinology, University of Colorado, Veterans Affairs Medical Center, Denver (M.E.W.); the Division of Diabetes and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan (K.T.); and the Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. (C.M.R., J.D.C.).

Ms. Shattuck and Dr. Välimäki contributed equally to this article.

Address reprint requests to Dr. Arnold at the Center for Molecular Medicine, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030-3101, or at molecularmedicine{at}uchc.edu, or to Dr. Larsson at catharina.larsson{at}cmm.ki.se.

Full Text of this Article

This article has been cited by other articles:

• Yang, Y.-J., Han, J.-W., Youn, H.-D., Cho, E.-J. (2009). The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression. Nucleic Acids Res 0: gkp991v1-gkp991 [Abstract] [Full Text]  
• Hahn, M. A, McDonnell, J., Marsh, D. J (2009). The effect of disease-associated HRPT2 mutations on splicing. J Endocrinol 201: 387-396 [Abstract] [Full Text]  
• Eastell, R., Arnold, A., Brandi, M. L., Brown, E. M., D'Amour, P., Hanley, D. A., Rao, D. S., Rubin, M. R., Goltzman, D., Silverberg, S. J., Marx, S. J., Peacock, M., Mosekilde, L., Bouillon, R., Lewiecki, E. M. (2009). Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop. J. Clin. Endocrinol. Metab. 94: 340-350 [Abstract] [Full Text]  
• Howell, V. M., Gill, A., Clarkson, A., Nelson, A. E., Dunne, R., Delbridge, L. W., Robinson, B. G., Teh, B. T., Gimm, O., Marsh, D. J. (2009). Accuracy of Combined Protein Gene Product 9.5 and Parafibromin Markers for Immunohistochemical Diagnosis of Parathyroid Carcinoma. J. Clin. Endocrinol. Metab. 94: 434-441 [Abstract] [Full Text]  
• Rozenblatt-Rosen, O., Nagaike, T., Francis, J. M., Kaneko, S., Glatt, K. A., Hughes, C. M., LaFramboise, T., Manley, J. L., Meyerson, M. (2009). The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors. Proc. Natl. Acad. Sci. USA 106: 755-760 [Abstract] [Full Text]  
• Masi, G., Barzon, L., Iacobone, M., Viel, G., Porzionato, A., Macchi, V., De Caro, R., Favia, G., Palu, G. (2008). Clinical, genetic, and histopathologic investigation of CDC73-related familial hyperparathyroidism. Endocr Relat Cancer 15: 1115-1126 [Abstract] [Full Text]  
• Lin, L., Zhang, J.-H., Panicker, L. M., Simonds, W. F. (2008). The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proc. Natl. Acad. Sci. USA 105: 17420-17425 [Abstract] [Full Text]  
• Rubin, M. R, Bilezikian, J. P, Birken, S., Silverberg, S. J (2008). Human chorionic gonadotropin measurements in parathyroid carcinoma. Eur J Endocrinol 159: 469-474 [Abstract] [Full Text]  
• Wang, P., Bowl, M. R., Bender, S., Peng, J., Farber, L., Chen, J., Ali, A., Zhang, Z., Alberts, A. S., Thakker, R. V., Shilatifard, A., Williams, B. O., Teh, B. T. (2008). Parafibromin, a Component of the Human PAF Complex, Regulates Growth Factors and Is Required for Embryonic Development and Survival in Adult Mice. Mol. Cell. Biol. 28: 2930-2940 [Abstract] [Full Text]  
• Weber, F., Eng, C. (2008). Update on the Molecular Diagnosis of Endocrine Tumors: Toward -omics-Based Personalized Healthcare?. J. Clin. Endocrinol. Metab. 93: 1097-1104 [Abstract] [Full Text]  
• Selvarajan, S, Sii, L-H, Lee, A, Yip, G, Bay, B-H, Tan, M-H, Teh, B-T, Tan, P-H (2008). Parafibromin expression in breast cancer: a novel marker for prognostication?. J. Clin. Pathol. 61: 64-67 [Abstract] [Full Text]  
• Cetani, F, Pardi, E, Ambrogini, E, Viacava, P, Borsari, S, Lemmi, M, Cianferotti, L, Miccoli, P, Pinchera, A, Arnold, A, Marcocci, C (2007). Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation. Endocr Relat Cancer 14: 493-499 [Abstract] [Full Text]  
• Juhlin, C C, Villablanca, A, Sandelin, K, Haglund, F, Nordenstrom, J, Forsberg, L, Branstrom, R, Obara, T, Arnold, A, Larsson, C, Hoog, A (2007). Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification. Endocr Relat Cancer 14: 501-512 [Abstract] [Full Text]  
• Cetani, F., Ambrogini, E., Viacava, P., Pardi, E., Fanelli, G., Naccarato, A. G., Borsari, S., Lemmi, M., Berti, P., Miccoli, P., Pinchera, A., Marcocci, C. (2007). Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma?. Eur J Endocrinol 156: 547-554 [Abstract] [Full Text]  
• Raue, F., Frank-Raue, K. (2007). Primary hyperparathyroidism--what the nephrologist should know--an update. Nephrol Dial Transplant 22: 696-699 [Full Text]  
• Lin, L., Czapiga, M., Nini, L., Zhang, J.-H., Simonds, W. F. (2007). Nuclear Localization of the Parafibromin Tumor Suppressor Protein Implicated in the Hyperparathyroidism-Jaw Tumor Syndrome Enhances Its Proapoptotic Function. Mol Cancer Res 5: 183-193 [Abstract] [Full Text]  
• Howell, V. M., Cardinal, J. W., Richardson, A.-L., Gimm, O., Robinson, B. G., Marsh, D. J. (2006). Rapid Mutation Screening for HRPT2 and MEN1 Mutations Associated with Familial and Sporadic Primary Hyperparathyroidism. J. Mol. Diagn. 8: 559-566 [Abstract] [Full Text]  
• Marx, S. J., Simonds, W. F. (2006). Imaging to detect early endocrine cancers.. J. Clin. Endocrinol. Metab. 91: 2861-2863 [Full Text]  
• Guarnieri, V., Scillitani, A., Muscarella, L. A., Battista, C., Bonfitto, N., Bisceglia, M., Minisola, S., Mascia, M. L., D'Agruma, L., Cole, D. E. C. (2006). Diagnosis of Parathyroid Tumors in Familial Isolated Hyperparathyroidism with HRPT2 Mutation: Implications for Cancer Surveillance. J. Clin. Endocrinol. Metab. 91: 2827-2832 [Abstract] [Full Text]  
• Juhlin, C, Larsson, C, Yakoleva, T, Leibiger, I, Leibiger, B, Alimov, A, Weber, G, Hoog, A, Villablanca, A (2006). Loss of parafibromin expression in a subset of parathyroid adenomas.. Endocr Relat Cancer 13: 509-523 [Abstract] [Full Text]  
• Rubin, M. R., Silverberg, S. J. (2005). HRPT2 in Parathyroid Cancer: A Piece of the Puzzle. J. Clin. Endocrinol. Metab. 90: 5505-5507 [Full Text]  
• Krebs, L. J., Shattuck, T. M., Arnold, A. (2005). HRPT2 Mutational Analysis of Typical Sporadic Parathyroid Adenomas. J. Clin. Endocrinol. Metab. 90: 5015-5017 [Abstract] [Full Text]  
• Marx, S. J., Simonds, W. F. (2005). Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes. Endocr. Rev. 26: 615-661 [Abstract] [Full Text]  
• Bradley, K J, Cavaco, B M, Bowl, M R, Harding, B, Young, A, Thakker, R V (2005). Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. J. Med. Genet. 42: e51-e51 [Abstract] [Full Text]  
• Yart, A., Gstaiger, M., Wirbelauer, C., Pecnik, M., Anastasiou, D., Hess, D., Krek, W. (2005). The HRPT2 Tumor Suppressor Gene Product Parafibromin Associates with Human PAF1 and RNA Polymerase II. Mol. Cell. Biol. 25: 5052-5060 [Abstract] [Full Text]  
• Forsberg, L., Bjorck, E., Hashemi, J., Zedenius, J., Hoog, A., Farnebo, L.-O., Reimers, M., Larsson, C. (2005). Distinction in gene expression profiles demonstrated in parathyroid adenomas by high-density oligoarray technology. Eur J Endocrinol 152: 459-470 [Abstract] [Full Text]  
• Moon, S.-D., Park, J.-H., Kim, E.-M., Kim, J.-H., Han, J.-H., Yoo, S.-J., Yoon, K.-H., Kang, M.-I., Lee, K.-W., Son, H.-Y., Kang, S.-K., Oh, S.-J., Kim, K.-M., Yoon, S.-J. K., Park, J.-G., Kim, I.-J., Kang, H. C., Hong, S.-W., Kim, K.-R., Cha, B.-Y. (2005). A Novel IVS2-1G>A Mutation Causes Aberrant Splicing of the HRPT2 Gene in a Family with Hyperparathyroidism-Jaw Tumor Syndrome. J. Clin. Endocrinol. Metab. 90: 878-883 [Abstract] [Full Text]  
• Rozenblatt-Rosen, O., Hughes, C. M., Nannepaga, S. J., Shanmugam, K. S., Copeland, T. D., Guszczynski, T., Resau, J. H., Meyerson, M. (2005). The Parafibromin Tumor Suppressor Protein Is Part of a Human Paf1 Complex. Mol. Cell. Biol. 25: 612-620 [Abstract] [Full Text]  
• Cetani, F., Pardi, E., Borsari, S., Viacava, P., Dipollina, G., Cianferotti, L., Ambrogini, E., Gazzerro, E., Colussi, G., Berti, P., Miccoli, P., Pinchera, A., Marcocci, C. (2004). Genetic Analyses of the HRPT2 Gene in Primary Hyperparathyroidism: Germline and Somatic Mutations in Familial and Sporadic Parathyroid Tumors. J. Clin. Endocrinol. Metab. 89: 5583-5591 [Abstract] [Full Text]  
• Tan, M.-H., Morrison, C., Wang, P., Yang, X., Haven, C. J., Zhang, C., Zhao, P., Tretiakova, M. S., Korpi-Hyovalti, E., Burgess, J. R., Soo, K. C., Cheah, W.-K., Cao, B., Resau, J., Morreau, H., Teh, B. T. (2004). Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma. Clin. Cancer Res. 10: 6629-6637 [Abstract] [Full Text]  
• Betea, D., Bradwell, A. R., Harvey, T. C., Mead, G. P., Schmidt-Gayk, H., Ghaye, B., Daly, A. F., Beckers, A. (2004). Hormonal and Biochemical Normalization and Tumor Shrinkage Induced by Anti-Parathyroid Hormone Immunotherapy in a Patient with Metastatic Parathyroid Carcinoma. J. Clin. Endocrinol. Metab. 89: 3413-3420 [Abstract] [Full Text]