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Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas
- Publication Year :
- 2017
-
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.
- Subjects :
- Adenoma
Adult
Male
endocrine system diseases
Endocrinology, Diabetes and Metabolism
Primary hyperparathyroidism
CDKN1B
MEN1-like
MEN4
Endocrinology
030209 endocrinology & metabolism
Biology
Gene mutation
medicine.disease_cause
Germline
NO
Loss of heterozygosity
03 medical and health sciences
0302 clinical medicine
Germline mutation
Proto-Oncogene Proteins
medicine
Humans
MEN1
Gene
Middle Aged
medicine.disease
Hyperparathyroidism, Primary
Immunohistochemistry
Diabetes and Metabolism
Parathyroid Neoplasms
030220 oncology & carcinogenesis
Mutation
Cancer research
Female
Carcinogenesis
Cyclin-Dependent Kinase Inhibitor p27
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....27f27c716363ac423690dfe9ed5c9b69