Loss of p27 expression is associated with Emphasi

Authors: Simona Borsari Elena Pardi Natalia S Pellegata Misu Lee Federica Saponaro Liborio Torregrossa Fulvio Basolo Elena Paltrinieri Maria Chiara Zatelli Gabriele Materazzi Paolo Miccoli Claudio Marcocci Filomena Cetani

Publish Date: 2016/04/02

Volume: 55, Issue: 2, Pages: 386-397

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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 c80CT c29 26delAGAG c397CA were identified in 3/147 patients Reduction of CDKN1B gene transcription rate was demonstrated in vitro for the novel c80CT and the c29 26delAGAG variants Loss of p27 expression was detected in the tumor carrying the c29 26delAGAG variant Two tumors carrying the CDKN1B variants also harbored a MEN1 mutation Fiftyfour percent of 50 CDKN1B mutationnegative 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 downregulation of p27 expression through the inhibition of CDKN1B gene transcriptionWe 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

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