Skip to main content

Advertisement

SpringerLink
Log in

Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas

  • Endocrine Genetics/Epigenetics
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

MEN1 is the main gene responsible for tumorigenesis of syndromic and sporadic primary hyperparathyroidism (PHPT). Germline mutations of the CDKN1B/p27Kip gene have been associated with multiple endocrine tumors in rats and humans. To evaluate the involvement of the CDKN1B gene and its relationship with MEN1 in sporadic PHPT, we carried out sequencing and loss of heterozygosity analyses of the CDKN1B gene in 147 sporadic parathyroid adenomas. p27 immunohistochemistry and genetic screening of the MEN1 gene were performed in 50 cases. Three germline CDKN1B variants (c.-80C>T, c.-29_-26delAGAG, c.397C>A) were identified in 3/147 patients. Reduction of CDKN1B gene transcription rate was demonstrated in vitro for the novel c.-80C>T and the c.-29_-26delAGAG variants. Loss of p27 expression was detected in the tumor carrying the c.-29_-26delAGAG variant. Two tumors carrying the CDKN1B variants also harbored a MEN1 mutation. Fifty-four percent of 50 CDKN1B mutation-negative tumors had a reduction of p27 nuclear staining. Somatic MEN1 mutations, identified in 15/50 samples, significantly segregated in tumors negative for nuclear and cytoplasmic p27 staining. The germline nature of the CDKN1B mutations suggests that they might predispose to PHPT. The lack of somatic CDKN1B mutations in our samples points to a rare involvement in parathyroid adenomas, despite the frequent loss of nuclear p27 expression. MEN1 biallelic inactivation seems to be directly related to down-regulation of p27 expression through the inhibition of CDKN1B gene transcription.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. F. Cetani, E. Pardi, S. Borsari, C. Marcocci, Molecular pathogenesis of primary hyperparathyroidism. J. Endocrinol. Investig. 34, 35–39 (2011)

    CAS  Google Scholar 

  2. J. Costa-Guda, A. Arnold, Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol. Cell. Endocrinol. 386, 46–54 (2014)

    Article  CAS  PubMed  Google Scholar 

  3. M.C. Lemos, R.V. Thakker, Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 29, 22–32 (2008)

    Article  CAS  PubMed  Google Scholar 

  4. E. Pardi, C. Marcocci, S. Borsari, F. Saponaro, L. Torregrossa, M. Tancredi, B. Raspini, F. Basolo, F. Cetani, Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 98, 2800–2810 (2013)

    Article  CAS  PubMed  Google Scholar 

  5. 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, E1774–E1781 (2012)

    Article  CAS  PubMed  Google Scholar 

  6. L.F. Starker, A.L. 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, 612–615 (2012)

    Article  CAS  PubMed  Google Scholar 

  7. L.F. Starker, A. Delgado-Verdugo, R. Udelsman, P. Bjorklund, T. Carling, Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism. Endocrine 38, 397–401 (2010)

    Article  CAS  PubMed  Google Scholar 

  8. S.K. Karnik, C.M. Hughes, X. Gu, O. Rozenblatt-Rosen, G.W. McLean, Y. Xiong, M. Meyerson, S.K. Kim, Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl. Acad. Sci. U.S.A. 102, 14659–14664 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. T.A. Milne, C.M. Hughes, R. Lloyd, Z. Yang, O. Rozenblatt-Rosen, Y. Dou, R.W. Schnepp, C. Krankel, V.A. Livolsi, D. Gibbs, X. Hua, R.G. Roeder, M. Meyerson, J.L. Hess, Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 102, 749–754 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. G. Viglietto, M.L. Motti, A. Fusco, Understanding p27(kip1) deregulation in cancer: down-regulation or mislocalization. Cell Cycle 1, 394–400 (2002)

    Article  CAS  PubMed  Google Scholar 

  11. B. Belletti, G. Baldassarre, New light on p27(kip1) in breast cancer. Cell Cycle 11, 3701–3702 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. S. Dietrich, J. Hullein, S.C. Lee, B. Hutter, D. Gonzalez, S. Jayne, M.J. Dyer, M. Oles, M. Else, X. Liu, M. Slabicki, B. Wu, X. Troussard, J. Durig, M. Andrulis, C. Dearden, C. von Kalle, M. Granzow, A. Jauch, S. Frohling, W. Huber, M. Meggendorfer, T. Haferlach, A.D. Ho, D. Richter, B. Brors, H. Glimm, E. Matutes, O. Abdel, T. Zenz, Recurrent CDKN1B (p27) mutations in hairy cell leukemia. Blood 126, 1005–1008 (2015)

    Article  CAS  PubMed  Google Scholar 

  13. J.E. Maxwell, S.K. Sherman, G. Li, A.B. Choi, A.M. Bellizzi, T.M. O’Dorisio, J.R. Howe, Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors. Cancer Genet. 208(11), 564–570 (2015)

    Article  CAS  Google Scholar 

  14. R. Morosetti, N. Kawamata, A.F. Gombart, C.W. Miller, Y. Hatta, T. Hirama, J.W. Said, M. Tomonaga, H.P. Koeffler, Alterations of the p27KIP1 gene in non-Hodgkin’s lymphomas and adult T-cell leukemia/lymphoma. Blood 86, 1924–1930 (1995)

    CAS  PubMed  Google Scholar 

  15. J. Crona, T. Gustavsson, O. Norlen, K. Edfeldt, T. Akerstrom, G. Westin, P. Hellman, P. Bjorklund, P. Stalberg, Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors. Ann. Surg. Oncol. 45(12), 1483–1486 (2015)

    Google Scholar 

  16. M.L. Fero, E. Randel, K.E. Gurley, J.M. Roberts, C.J. Kemp, The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396, 177–180 (1998)

    Article  CAS  PubMed  Google Scholar 

  17. J. Philipp-Staheli, S.R. Payne, C.J. Kemp, p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp. Cell Res. 264, 148–168 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. J. Slingerland, M. Pagano, Regulation of the Cdk inhibitor p27 and its deregulation in cancer. J. Cell. Physiol. 183, 10–17 (2000)

    Article  CAS  PubMed  Google Scholar 

  19. M. Lee, N.S. Pellegata, Multiple endocrine neoplasia syndromes associated with mutation of p27. J. Endocrinol. Investig. 36, 781–787 (2013)

    CAS  Google Scholar 

  20. 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, E701–E706 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. T. Gluick, Z. Yuan, S.K. Libutti, S.J. Marx, Mutations in CDKN2C (p18) and CDKN2D (p19) may cause sporadic parathyroid adenoma. Endocr. Relat. Cancer 20, L27–L29 (2013)

    Article  CAS  PubMed  Google Scholar 

  22. F. Cetani, E. Pardi, A. Giovannetti, P. Cerrai, S. Borsari, E. Vignali, A. Picone, L. Cianferotti, P. Miccoli, A. Pinchera, C. Marcocci, Six novel MEN1 gene mutations in sporadic parathyroid tumors. Hum. Mutat. 16, 445 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. 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. U.S.A. 103, 15558–15563 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. S. Sambugaro, M. Di Ruvo, M.R. Ambrosio, N.S. Pellegata, M. Bellio, A. Guerra, M. Buratto, M.P. Foschini, F. Tagliati, E. Degli Uberti, M.C. Zatelli, Early onset acromegaly associated with a novel deletion in CDKN1B 5′UTR region. Endocrine 49, 58–64 (2015)

    Article  CAS  PubMed  Google Scholar 

  25. D. Malanga, S. De Gisi, M. Riccardi, M. Scrima, C. De Marco, M. Robledo, G. Viglietto, Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype. Eur. J. Endocrinol. 166, 551–560 (2012)

    Article  CAS  PubMed  Google Scholar 

  26. 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, 1826–1834 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. E. Pardi, S. Mariotti, N.S. Pellegata, K. Benfini, S. Borsari, F. Saponaro, L. Torregrossa, A. Cappai, C. Satta, M. Mastinu, C. Marcocci, F. Cetani, Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4). Endocr. Connect. 4, 1–8 (2015)

    Article  Google Scholar 

  28. M.S. Elston, G.Y. Meyer-Rochow, M. Dray, M. Swarbrick, J.V. Conaglen, Early onset primary hyperparathyroidism associated with a novel germline mutation in CDKN1B. Case Rep. Endocrinol. 2015, 510985 (2015)

    PubMed  PubMed Central  Google Scholar 

  29. B.L. Chang, S.L. Zheng, S.D. Isaacs, K.E. Wiley, A. Turner, G. Li, P.C. Walsh, D.A. Meyers, W.B. Isaacs, J. Xu, A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer. Cancer Res. 64, 1997–1999 (2004)

    Article  CAS  PubMed  Google Scholar 

  30. W. Wang, M.R. Spitz, H. Yang, C. Lu, D.J. Stewart, X. Wu, Genetic variants in cell cycle control pathway confer susceptibility to lung cancer. Clin. Cancer Res. 13, 5974–5981 (2007)

    Article  CAS  PubMed  Google Scholar 

  31. H. Xiang, H. Li, W. Ge, W. Wu, M. Gao, W. Wang, L. Hong, D. Jiang, C. Zhang, Association of CDKN1B gene polymorphisms with susceptibility to breast cancer: a meta-analysis. Mol. Biol. Rep. 40, 6371–6377 (2013)

    Article  CAS  PubMed  Google Scholar 

  32. I. Landa, C. Montero-Conde, D. Malanga, S. De Gisi, G. Pita, L.J. Leandro-Garcia, L. Inglada-Perez, R. Leton, C. De Marco, C. Rodriguez-Antona, G. Viglietto, M. Robledo, Allelic variant at −79 (C > T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels. Endocr. Relat. Cancer 17, 317–328 (2010)

    Article  CAS  PubMed  Google Scholar 

  33. C. Verdelli, I. Forno, V. Vaira, S. Corbetta, Epigenetic alterations in human parathyroid tumors. Endocrine 49, 324–332 (2015)

    Article  CAS  PubMed  Google Scholar 

  34. J. Coleman, W.K. Miskimins, Structure and activity of the internal ribosome entry site within the human p27 Kip1 5′-untranslated region. RNA Biol. 6, 84–89 (2009)

    Article  CAS  PubMed  Google Scholar 

  35. M.J. Bugalho, R. Domingues, Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene. BMJ Case Rep. (2016). doi:10.1136/bcr-2015-213934

    Google Scholar 

  36. N.S. Pellegata, MENX and MEN4. Clin. (Sao Paulo) 67(Suppl 1), 13–18 (2012)

    Article  Google Scholar 

  37. K. Horiguchi, M. Yamada, T. Satoh, K. Hashimoto, J. Hirato, M. Tosaka, S. Yamada, M. Mori, Transcriptional activation of the mixed lineage leukemia-p27Kip1 pathway by a somatostatin analogue. Clin. Cancer Res. 15, 2620–2629 (2009)

    Article  CAS  PubMed  Google Scholar 

  38. S.K. Agarwal, M.B. Kester, L.V. Debelenko, C. Heppner, M.R. Emmert-Buck, M.C. Skarulis, J.L. Doppman, Y.S. Kim, I.A. Lubensky, Z. Zhuang, J.S. Green, S.C. Guru, P. Manickam, S.E. Olufemi, L.A. Liotta, S.C. Chandrasekharappa, F.S. Collins, A.M. Spiegel, A.L. Burns, S.J. Marx, Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum. Mol. Genet. 6, 1169–1175 (1997)

    Article  CAS  PubMed  Google Scholar 

  39. L. Shan, Y. Nakamura, M. Nakamura, T. Yokoi, M. Tsujimoto, R. Arima, T. Kameya, K. Kakudo, Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab. Investig. 78, 471–475 (1998)

    CAS  PubMed  Google Scholar 

  40. W. Bazzi, M. Renon, C. Vercherat, Z. Hamze, A. Lacheretz-Bernigaud, H. Wang, M. Blanc, C. Roche, A. Calender, J.A. Chayvialle, J.Y. Scoazec, M. Cordier-Bussat, MEN1 missense mutations impair sensitization to apoptosis induced by wild-type menin in endocrine pancreatic tumor cells. Gastroenterology 135, 1698–1709 (2008)

    Article  CAS  PubMed  Google Scholar 

  41. C. Nozieres, C.X. Zhang, A. Buffet, S. Dupasquier, R. Vargas-Poussou, M. Guillaud-Bataille, M. Cordier-Bussat, P. Ruszniewski, S. Christin-Maitre, A. Murat, L. Groussin, D. Vezzosi, C. Cardot-Bauters, V. Hervieu, M.O. Joly, S. Giraud, M.F. Odou, A.P. Gimenez-Roqueplo, P. Goudet, F. Borson-Chazot, A. Calender, e. Groupe francais des tumeurs, p.Ala541Thr variant of MEN1 gene: a non deleterious polymorphism or a pathogenic mutation? Ann. Endocrinol. (Paris) 75, 133–140 (2014)

    Article  Google Scholar 

  42. F. Bai, X.H. Pei, T. Nishikawa, M.D. Smith, Y. Xiong, p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. Mol. Cell. Biol. 27, 1495–1504 (2007)

    Article  CAS  PubMed  Google Scholar 

  43. I.M. Chu, L. Hengst, J.M. Slingerland, The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat. Rev. Cancer 8, 253–267 (2008)

    Article  CAS  PubMed  Google Scholar 

  44. R.V. Lloyd, L. Jin, X. Qian, E. Kulig, Aberrant p27kip1 expression in endocrine and other tumors. Am. J. Pathol. 150, 401–407 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. L.A. Erickson, L. Jin, P. Wollan, G.B. Thompson, J.A. van Heerden, R.V. Lloyd, Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27Kip1 protein. Am. J. Surg. Pathol. 23, 288–295 (1999)

    Article  CAS  PubMed  Google Scholar 

  46. M. Tokumoto, K. Tsuruya, K. Fukuda, H. Kanai, S. Kuroki, H. Hirakata, Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism. Kidney Int. 62, 1196–1207 (2002)

    Article  CAS  PubMed  Google Scholar 

  47. A. Stojadinovic, A. Hoos, A. Nissan, M.E. Dudas, C. Cordon-Cardo, A.R. Shaha, M.F. Brennan, B. Singh, R.A. Ghossein, Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis. Hum. Pathol. 34, 54–64 (2003)

    Article  PubMed  Google Scholar 

  48. N. Bergero, R. De Pompa, C. Sacerdote, G. Gasparri, M. Volante, G. Bussolati, M. Papotti, Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases. Hum. Pathol. 36, 908–914 (2005)

    Article  CAS  PubMed  Google Scholar 

  49. G.G. Fernandez-Ranvier, E. Khanafshar, D. Tacha, M. Wong, E. Kebebew, Q.Y. Duh, O.H. Clark, Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer 115, 334–344 (2009)

    Article  PubMed  Google Scholar 

  50. B.M. Erovic, L. Harris, M. Jamali, D.P. Goldstein, J.C. Irish, S.L. Asa, O. Mete, Biomarkers of parathyroid carcinoma. Endocr. Pathol. 23, 221–231 (2012)

    Article  CAS  PubMed  Google Scholar 

  51. M.I. Alvelos, J. Vinagre, E. Fonseca, E. Barbosa, J. Teixeira-Gomes, M. Sobrinho-Simoes, P. Soares, MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism. Eur. J. Endocrinol. 168, 119–128 (2013)

    Article  CAS  PubMed  Google Scholar 

  52. P.J. Newey, M.A. Nesbit, A.J. Rimmer, R.A. Head, C.M. Gorvin, M. Attar, L. Gregory, J.A. Wass, D. Buck, N. Karavitaki, A.B. Grossman, G. McVean, O. Ansorge, R.V. Thakker, Whole-exome sequencing studies of nonfunctioning pituitary adenomas. J. Clin. Endocrinol. Metab. 98, E796–E800 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. S. Fontaniere, H. Casse, P. Bertolino, C.X. Zhang, Analysis of p27(Kip1) expression in insulinomas developed in pancreatic beta-cell specific Men1 mutant mice. Fam. Cancer 5, 49–54 (2006)

    Article  CAS  PubMed  Google Scholar 

  54. S. Ogino, T. Kawasaki, A. Ogawa, G.J. Kirkner, M. Loda, C.S. Fuchs, Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype. Hum. Pathol. 38, 585–592 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. S. Corbetta, V. Vaira, V. Guarnieri, A. Scillitani, C. Eller-Vainicher, S. Ferrero, L. Vicentini, I. Chiodini, M. Bisceglia, P. Beck-Peccoz, S. Bosari, A. Spada, Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr. Relat. Cancer 17, 135–146 (2010)

    Article  CAS  PubMed  Google Scholar 

  56. C. le Sage, R. Nagel, D.A. Egan, M. Schrier, E. Mesman, A. Mangiola, C. Anile, G. Maira, N. Mercatelli, S.A. Ciafre, M.G. Farace, R. Agami, Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 26, 3699–3708 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  57. J. Lee, S.S. Kim, The function of p27 KIP1 during tumor development. Exp. Mol. Med. 41, 765–771 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. J.H.D. Bassett, S.A. Forbes, A.A.J. Pannett, S.E. Lloyd, P.T. Christie, C. Wooding, B. Harding, G.M. Besser, C.R. Edwards, J.P. Monson, J. Sampson, J.A.H. Wass, M.H. Wheeler, R.V. Thakker, Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am. J. Hum. Genet. 62, 232–244 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. C. Tanaka, K. Yoshimoto, S. Yamada, H. Nishioka, S. Li, M. Moritani, T. Yamaoka, M. Itakura, Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese. J. Clin. Endocr. Metab. 83(3), 960–965 (1998)

    CAS  PubMed  Google Scholar 

  60. I. Lemmens, W.J.M. Van de Ven, K. Kas, C.X. Zhang, S. Giraud, V. Wautot, N. Buisson, K. De Witte, J. Salandre, G. Lenoir, M. Pugeat, A. Calender, F. Parente, D. Quincey, P. Gaudray, M.J. De Wit, C.J.M. Lips, J.W.M. Höppener, S. Khodaei, A.L. Grant, G. Weber, S. Kytölä, B.T. Teh, F. Farnebo, C. Phelan, N. Hayward, C. Larsson, A.A.J. Pannett, S.A. Forbes, J.H. Duncan Bassett, R.V. Thakker, Identification of the multiple endocrine neoplasia type1 (MEN1) gene. The European Consortium on MEN1. Hum. Mol. Genet. 6(7), 1177–1183 (1997)

    Article  CAS  PubMed  Google Scholar 

  61. S. Giraud, C.X. Zhang, O. Serova-Sinilnikova, V. Wautot, J. Salandre, N. Buisson, C. Waterlot, C. Bauters, N. Porchet, J.-P. Aubert, P. Emy, G. Cadiot, B. Delemer, O. Chabre, P. Niccoli, F. Leprat, F. Duron, B. Emperauger, P. Cougard, P. Goudet, E. Sarfati, J.-P. Riou, S. Guichard, M. Rodier, A. Meyrier, P. Caron, M.-C. Vantyghem, M. Assayag, J.-L. Peix, M. Pugeat, V. Rohmer, M. Vallotton, G. Lenoir, P. Gaudray, C. Proye, B. Conte Devolx, P. Chanson, Y.Y. Shugart, D. Goldgar, A. Murat, A. Calender, Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am. J. Hum. Genet. 63, 455–467 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Drs. Antonella Picone, Antonella Meola, Silvia Chiavistelli for the help in the collection of parathyroid specimens. CDKN1B and MEN1 mutations were submitted to ClinVar database; accessions SCV000246271; SCV000246272; SCV000246273; SCV000246274; SCV000246275.

Funding

This work was supported by Grants from the University of Pisa (Fondi di Ateneo per la Ricerca) and Ministero dell’Istruzione, dell’Universita` e della Ricerca to C Marcocci (Grant Number 20094T89BR).

Author information

Author notes

  1. Elena Paltrinieri

    Present address: Department of Clinical Sciences and Community Health, University of Milan IRCCS Foundation Ca’ Granda Policlinico Hospital, Milan, Italy

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Simona Borsari, Elena Pardi, Federica Saponaro, Elena Paltrinieri & Claudio Marcocci

  2. Institute of Pathology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Ingolstaedter Landstrasse, Neuherberg, Germany

    Natalia S. Pellegata & Misu Lee

  3. Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

    Liborio Torregrossa, Fulvio Basolo, Gabriele Materazzi & Paolo Miccoli

  4. Department of Medical Sciences, Section of Endocrinology, University of Ferrara, Ferrara, Italy

    Maria Chiara Zatelli

  5. Endocrine Unit 2, University Hospital of Pisa, Via Paradisa, 2, 56124, Pisa, Italy

    Filomena Cetani

Authors
  1. Simona Borsari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Pardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia S. Pellegata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Misu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federica Saponaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liborio Torregrossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fulvio Basolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elena Paltrinieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Chiara Zatelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gabriele Materazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paolo Miccoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Claudio Marcocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Filomena Cetani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Filomena Cetani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Simona Borsari and Elena Pardi have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 43 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Borsari, S., Pardi, E., Pellegata, N.S. et al. Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas. Endocrine 55, 386–397 (2017). https://doi.org/10.1007/s12020-016-0941-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-0941-6

Keywords

Search

Navigation