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Allelic imbalance in sporadic parathyroid carcinoma and evidence for its de novo origins

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Abstract

Parathyroid cancer is a rare, clinically aggressive cause of primary hyperparathyroidism, and whether these malignancies generally evolve from pre-existing benign adenomas or arise de novo is unclear. Furthermore, while inactivation of the CDC73 (HRPT2) tumor suppressor gene, encoding parafibromin, is a major contributor, other genes essential to parathyroid carcinogenesis remain unknown. We sought to identify genomic regions potentially harboring such oncogenes or tumor suppressor genes, and to gain insight into the origins and molecular relationship of malignant versus benign parathyroid tumors. We performed genome-wide copy-number and loss of heterozygosity analysis using Affymetrix 50K SNP mapping arrays and/or comparative genomic hybridization on 16 primary parathyroid carcinomas, local recurrences or distant metastases, and matched normal controls, from 10 individuals. Recurrent regions of allelic loss were observed on chromosomes 1p, 3, and 13q suggesting that key parathyroid tumor suppressor genes are located in these chromosomal locations. Recurrent allelic gains were seen on chromosomes 1q and 16, suggesting the presence of parathyroid oncogenes on these chromosomes. Importantly, the most common alteration in benign parathyroid adenomas, loss of 11q, was not found as a recurrent change in the malignant parathyroid tissues. Molecular allelotyping using highly polymorphic microsatellite markers provided further confirmation that the prevalence of 11q loss is markedly and significantly lower in carcinomas as compared with adenomas. Our observations provide molecular support for the concept that sporadic parathyroid cancer usually arises de novo, rather than evolving from a pre-existing typical benign adenoma. Furthermore, these results help direct future investigation to ultimately determine which of the candidate genes in these chromosomal locations make significant contributions to the molecular pathogenesis of parathyroid cancer.

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References

  1. C. Marcocci, F. Cetani, M.R. Rubin, S.J. Silverberg, A. Pinchera, J.P. Bilezikian, Parathyroid carcinoma. J. Bone Miner. Res. 23(12), 1869–1880 (2008)

    Article  PubMed  CAS  Google Scholar 

  2. R.L. Apel, S.L. Asa, The Parathyroid Glands, in Endocrine pathology, ed. by V. LiVolsi, S. Asa (Churchill Livingstone, Philadelphia, 2002), pp. 103–147

    Google Scholar 

  3. E. Shane, Clinical review 122: parathyroid carcinoma. J. Clin. Endocrinol. Metab. 86(2), 485–493 (2001)

    Article  PubMed  CAS  Google Scholar 

  4. B. Vogelstein, E.R. Fearon, S.E. Kern, S.R. Hamilton, A.C. Preisinger, Y. Nakamura, R. White, Allelotype of colorectal carcinomas. Science 244(4901), 207–211 (1989)

    Article  PubMed  CAS  Google Scholar 

  5. J. Costa-Guda, A. Arnold, Hyperparathyroidism, in Genetics of bone biology and skeletal disease, ed. by R.V. Thakker, M.P. Whyte, J.A. Eisman, T. Igarashi (Academic Press, San Diego, 2013), pp. 397–408

    Chapter  Google Scholar 

  6. T. Motokura, T. Bloom, H.G. Kim, H. Juppner, J.V. Ruderman, H.M. Kronenberg, A. Arnold, A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350(6318), 512–515 (1991)

    Article  PubMed  CAS  Google Scholar 

  7. A. Arnold, The cyclin D1/PRAD1 oncogene in human neoplasia. J. Investig. Med. 43(6), 543–549 (1995)

    PubMed  CAS  Google Scholar 

  8. E.D. Hsi, L.R. Zukerberg, W.I. Yang, A. Arnold, Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J. Clin. Endocrinol. Metab. 81(5), 1736–1739 (1996)

    Article  PubMed  CAS  Google Scholar 

  9. S.C. Chandrasekharappa, S.C. Guru, P. Manickam, S.E. Olufemi, F.S. Collins, M.R. Emmert-Buck, L.V. Debelenko, Z. Zhuang, I.A. Lubensky, L.A. Liotta, J.S. Crabtree, Y. Wang, B.A. Roe, J. Weisemann, M.S. Boguski, S.K. Agarwal, M.B. Kester, Y.S. Kim, C. Heppner, Q. Dong, A.M. Spiegel, A.L. Burns, S.J. Marx, Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276(5311), 404–407 (1997)

    Article  PubMed  CAS  Google Scholar 

  10. J. Costa-Guda, I. Marinoni, S. Molatore, N.S. Pellegata, A. Arnold, Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 96(4), E701–E706 (2011)

    Article  PubMed  CAS  Google Scholar 

  11. N.S. Pellegata, L. Quintanilla-Martinez, H. Siggelkow, E. Samson, K. Bink, H. Hofler, F. Fend, J. Graw, M.J. Atkinson, Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 103(42), 15558–15563 (2006)

    Article  PubMed  CAS  Google Scholar 

  12. S.K. Agarwal, C.M. Mateo, S.J. Marx, Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J. Clin. Endocrinol. Metab. 94(5), 1826–1834 (2009)

    Article  PubMed  CAS  Google Scholar 

  13. P. Bjorklund, D. Lindberg, G. Akerstrom, G. Westin, Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients. Mol. Cancer 7, 53 (2008)

    Article  PubMed  Google Scholar 

  14. V. Guarnieri, F. Baorda, C. Battista, M. Bisceglia, T. Balsamo, E. Gruppioni, M. Fiorentino, L.A. Muscarella, M. Coco, R. Barbano, S. Corbetta, A. Spada, D.E. Cole, L. Canaff, G.N. Hendy, M. Carella, A. Scillitani, A rare S33C mutation of CTNNB1 encoding beta-catenin in a parathyroid adenoma found in an Italian primary hyperparathyroid cohort. Endocrine 41(1), 152–155 (2012). doi:10.1007/s12020-011-9558-y

    Article  PubMed  CAS  Google Scholar 

  15. L.F. Starker, A. Fonseca, G. Akerstrom, P. Bjorklund, G. Westin, T. Carling, Evidence of a stabilizing mutation of beta-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas. Endocrine 42(3), 612–615 (2012). doi:10.1007/s12020-012-9690-3

    Article  PubMed  CAS  Google Scholar 

  16. M.K. Cromer, L.F. Starker, M. Choi, R. Udelsman, C. Nelson-Williams, R.P. Lifton, T. Carling, Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J. Clin. Endocrinol. Metab. 97(9), E1774–E1781 (2012). doi:10.1210/jc.2012-1743

    Article  PubMed  CAS  Google Scholar 

  17. P.J. Newey, M.A. Nesbit, A.J. Rimmer, M. Attar, R.T. Head, P.T. Christie, C.M. Gorvin, M. Stechman, L. Gregory, R. Mihai, G. Sadler, G. McVean, D. Buck, R.V. Thakker, Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J. Clin. Endocrinol. Metab. 97(10), E1995–E2005 (2012). doi:10.1210/jc.2012-2303

    Article  PubMed  CAS  Google Scholar 

  18. T.M. Shattuck, S. Valimaki, T. Obara, R.D. Gaz, O.H. Clark, D. Shoback, M.E. Wierman, K. Tojo, C.M. Robbins, J.D. Carpten, L.O. Farnebo, C. Larsson, A. Arnold, Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N. Engl. J. Med. 349(18), 1722–1729 (2003)

    Article  PubMed  CAS  Google Scholar 

  19. F. Cetani, E. Pardi, S. Borsari, P. Viacava, G. Dipollina, L. Cianferotti, E. Ambrogini, E. Gazzerro, G. Colussi, P. Berti, P. Miccoli, A. Pinchera, C. Marcocci, Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J. Clin. Endocrinol. Metab. 89(11), 5583–5591 (2004)

    Article  PubMed  CAS  Google Scholar 

  20. V.M. Howell, C.J. Haven, K. Kahnoski, S.K. Khoo, D. Petillo, J. Chen, G.J. Fleuren, B.G. Robinson, L.W. Delbridge, J. Philips, A.E. Nelson, U. Krause, K. Hammje, H. Dralle, C. Hoang-Vu, O. Gimm, D.J. Marsh, H. Morreau, B.T. Teh, HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J. Med. Genet. 40(9), 657–663 (2003)

    Article  PubMed  CAS  Google Scholar 

  21. L.J. Krebs, T.M. Shattuck, A. Arnold, HRPT2 mutational analysis of typical sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 90(9), 5015–5017 (2005)

    Article  PubMed  CAS  Google Scholar 

  22. J.D. Chen, C. Morrison, C. Zhang, K. Kahnoski, J.D. Carpten, B.T. Teh, Hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 253(6), 634–642 (2003)

    Article  PubMed  CAS  Google Scholar 

  23. K.J. Bradley, M.R. Hobbs, I.D. Buley, J.D. Carpten, B.M. Cavaco, J.E. Fares, P. Laidler, S. Manek, C.M. Robbins, I.S. Salti, N.W. Thompson, C.E. Jackson, R.V. Thakker, Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 257(1), 18–26 (2005). doi:10.1111/j.1365-2796.2004.01421.x

    Article  PubMed  CAS  Google Scholar 

  24. S.I. Roth, Pathology of the parathyroids in hyperparathyroidism. Discussion of recent advances in the anatomy and pathology of the parathyroid glands. Arch. Pathol. 73, 495–510 (1962)

    PubMed  CAS  Google Scholar 

  25. Y. Nannya, M. Sanada, K. Nakazaki, N. Hosoya, L. Wang, A. Hangaishi, M. Kurokawa, S. Chiba, D.K. Bailey, G.C. Kennedy, S. Ogawa, A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res. 65(14), 6071–6079 (2005)

    Article  PubMed  CAS  Google Scholar 

  26. N. Palanisamy, Y. Imanishi, P.H. Rao, H. Tahara, R.S. Chaganti, A. Arnold, Novel chromosomal abnormalities identified by comparative genomic hybridization in parathyroid adenomas. J. Clin. Endocrinol. Metab. 83(5), 1766–1770 (1998)

    Article  PubMed  CAS  Google Scholar 

  27. T.M. Shattuck, J. Costa, M. Bernstein, R.T. Jensen, D.C. Chung, A. Arnold, Mutational analysis of Smad3, a candidate tumor suppressor implicated in TGF-beta and menin pathways, in parathyroid adenomas and enteropancreatic endocrine tumors. J. Clin. Endocrinol. Metab. 87(8), 3911–3914 (2002)

    Article  PubMed  CAS  Google Scholar 

  28. K.A. Aldinger, R.C. Hickey, M.L. Ibanez, N.A. Samaan, Parathyroid carcinoma: a clinical study of seven cases of functioning and two cases of nonfunctioning parathyroid cancer. Cancer 49(2), 388–397 (1982)

    Article  PubMed  CAS  Google Scholar 

  29. Y. Berland, M. Olmer, G. Lebreuil, J. Grisoli, Parathyroid carcinoma, adenoma and hyperplasia in a case of chronic renal insufficiency on dialysis. Clin. Nephrol. 18(3), 154–158 (1982)

    PubMed  CAS  Google Scholar 

  30. C.E. Desch, G. Arsensis, P.D. Woolf, A.G. May, J.M. Amatruda, Parathyroid hyperplasia and carcinoma within one gland. Am. J. Med. 77(1), 131–134 (1984)

    Article  PubMed  CAS  Google Scholar 

  31. P. Haghighi, R.W. Astarita, H.T. Wepsic, P.L. Wolf, Concurrent primary parathyroid hyperplasia and parathyroid carcinoma. Arch. Pathol. Lab. Med. 107(7), 349–350 (1983)

    PubMed  CAS  Google Scholar 

  32. T. Murayama, K. Kawabe, M. Tagami, A case of parathyroid carcinoma concurred with hyperplasia: an electron microscopic study. J. Urol. 118(1 Pt 1), 126–127 (1977)

    PubMed  CAS  Google Scholar 

  33. S.K. Agarwal, E. Schrock, M.B. Kester, A.L. Burns, C.S. Heffess, T. Ried, S.J. Marx, Comparative genomic hybridization analysis of human parathyroid tumors. Cancer Genet. Cytogenet. 106(1), 30–36 (1998)

    Article  PubMed  CAS  Google Scholar 

  34. J. Costa-Guda, E. H. Samander, A. Arnold, Loss of heterozygosity analysis of parathyroid adenomas by single nucleotide polymorphism arrays. Paper presented at the Proceedings of the Annual Meeting of the American Association for Cancer Research

  35. F. Farnebo, S. Kytola, B.T. Teh, T. Dwight, F.K. Wong, A. Hoog, M. Elvius, W.S. Wassif, N.W. Thompson, L.O. Farnebo, K. Sandelin, C. Larsson, Alternative genetic pathways in parathyroid tumorigenesis. J. Clin. Endocrinol. Metab. 84(10), 3775–3780 (1999)

    Article  PubMed  CAS  Google Scholar 

  36. J.L. Hunt, S.E. Carty, J.H. Yim, J. Murphy, L. Barnes, Allelic loss in parathyroid neoplasia can help characterize malignancy. Am. J. Surg. Pathol. 29(8), 1049–1055 (2005)

    PubMed  Google Scholar 

  37. H. Tahara, A.P. Smith, R.D. Gas, V.L. Cryns, A. Arnold, Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas. Cancer Res. 56(3), 599–605 (1996)

    PubMed  CAS  Google Scholar 

  38. S. Kytola, F. Farnebo, T. Obara, J. Isola, L. Grimelius, L.O. Farnebo, K. Sandelin, C. Larsson, Patterns of chromosomal imbalances in parathyroid carcinomas. Am. J. Pathol. 157(2), 579–586 (2000)

    Article  PubMed  CAS  Google Scholar 

  39. A. Khan, A. Grey, D. Shoback, Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J. Clin. Endocrinol. Metab. 94(2), 373–381 (2009). doi:10.1210/jc.2008-1762

    Article  PubMed  CAS  Google Scholar 

  40. J.D. Carpten, C.M. Robbins, A. Villablanca, L. Forsberg, S. Presciuttini, J. Bailey-Wilson, W.F. Simonds, E.M. Gillanders, A.M. Kennedy, J.D. Chen, S.K. Agarwal, R. Sood, M.P. Jones, T.Y. Moses, C. Haven, D. Petillo, P.D. Leotlela, B. Harding, D. Cameron, A.A. Pannett, A. Hoog, H. Heath 3rd, L.A. James-Newton, B. Robinson, R.J. Zarbo, B.M. Cavaco, W. Wassif, N.D. Perrier, I.B. Rosen, U. Kristoffersson, P.D. Turnpenny, L.O. Farnebo, G.M. Besser, C.E. Jackson, H. Morreau, J.M. Trent, R.V. Thakker, S.J. Marx, B.T. Teh, C. Larsson, M.R. Hobbs, HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 32(4), 676–680 (2002)

    Article  PubMed  CAS  Google Scholar 

  41. V. Guarnieri, A. Scillitani, L.A. Muscarella, C. Battista, N. Bonfitto, M. Bisceglia, S. Minisola, M.L. Mascia, L. D’Agruma, D.E. Cole, Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J. Clin. Endocrinol. Metab. 91(8), 2827–2832 (2006)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We wish to thank Kristin Corrado and John Glynn for their expert technical assistance. This study was supported in part by NIH grants DK066411 and DHHS/NIDCR 5T32-DE07302, and by the Murray-Heilig Fund in Molecular Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. University of Connecticut Health Center, Farmington, CT, USA

    Jessica Costa-Guda, Yasuo Imanishi & Andrew Arnold

  2. Osaka City University Graduate School of Medicine, Osaka, Japan

    Yasuo Imanishi

  3. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Nallasivam Palanisamy & R. S. K. Chaganti

  4. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Norihiko Kawamata & H. Phillip Koeffler

  5. Center for Molecular Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030-3101, USA

    Andrew Arnold

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  1. Jessica Costa-Guda
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  2. Yasuo Imanishi
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Correspondence to Andrew Arnold.

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Costa-Guda, J., Imanishi, Y., Palanisamy, N. et al. Allelic imbalance in sporadic parathyroid carcinoma and evidence for its de novo origins. Endocrine 44, 489–495 (2013). https://doi.org/10.1007/s12020-013-9903-4

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