title: Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas.
abstract: MEN1 is the main gene responsible for tumorigenesis of syndromic and sporadic primary hyperparathyroidism (PHPT). Germline mutations of the CDKN1B/p27Kipgene 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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Borsari
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pardi
authors.affiliation: Institute of Pathology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Ingolstaedter Landstrasse, Neuherberg, Germany.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
authors.affiliation: Institute of Pathology, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Ingolstaedter Landstrasse, Neuherberg, Germany.
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Saponaro
authors.affiliation: Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Liborio
authors.initials: L
authors.lastname: Torregrossa
authors.affiliation: Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.|Department of Clinical Sciences and Community Health, University of Milan IRCCS Foundation Ca' Granda Policlinico Hospital, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Paltrinieri
authors.affiliation: Department of Medical Sciences, Section of Endocrinology, University of Ferrara, Ferrara, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.affiliation: Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.affiliation: Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Marcocci
authors.affiliation: Endocrine Unit 2, University Hospital of Pisa, Via Paradisa, 2, 56124, Pisa, Italy. cetani@endoc.med.unipi.it.
authors.forename: Filomena
authors.initials: F
authors.lastname: Cetani
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: CDKN1B; MEN1-like; MEN4; Primary hyperparathyroidism