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Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours.
Clin Endocrinol (Oxf). 2008 Feb; 68(2):271-7.CE

Abstract

OBJECTIVE

Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene at 11q13, enhances transcription of the cyclin-dependent kinase inhibitors (CDIs), CDKN2C (p18) and CDKN1B (p27) in mouse pancreatic islets, and inactivation of menin reduced CDKN2B (p15) expression in this mouse model. Here, we have compared the relative mRNA expression level and CpG methylation status of p18, p27 and p15 in 18 pancreatic endocrine tumours (PETs) with or without MEN1 gene mutations.

DESIGN

Real-time quantitative PCR, DNA sequencing and pyrosequencing methylation analysis were employed.

RESULTS

The p18 gene was expressed in 15 out of the 18 analysed PETs. The expression level was within the range of the normal pancreatic tissues or higher. Of the three remaining tumours with no expression, two displayed loss of heterozygocity (LOH) at 11q13, one derived from a MEN1 patient. The p27 gene was expressed in all PETs at a level higher than the normal pancreatic tissues, except for one tumour. Promoter methylation was not detected for p18 and p27. p15 expression was undetectable in 8/18 (44%) of the PETs, and no general relations to tumour syndrome, malignancy or MEN1 gene mutations were evident. This was not due to homozygous gene deletions, but the p15 promoter was hypermethylated in two insulinomas. No mutations were found in the p15 gene.

CONCLUSIONS

Expression of p15, p18 and p27 was not generally related to the MEN1 gene mutational status of the investigated 18 PETs. The p15 gene was silenced by promoter hypermethylation in two tumours. Dysregulation of menin and the CDIs are important in PET tumorigenesis, and their interrelations remain to be elucidated.

Authors+Show Affiliations

Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, Uppsala, Sweden.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17803708

Citation

Lindberg, Daniel, et al. "Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA Expression, and CpG Methylation Status in Sporadic and MEN1-associated Pancreatic Endocrine Tumours." Clinical Endocrinology, vol. 68, no. 2, 2008, pp. 271-7.
Lindberg D, Akerström G, Westin G. Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clin Endocrinol (Oxf). 2008;68(2):271-7.
Lindberg, D., Akerström, G., & Westin, G. (2008). Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clinical Endocrinology, 68(2), 271-7.
Lindberg D, Akerström G, Westin G. Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA Expression, and CpG Methylation Status in Sporadic and MEN1-associated Pancreatic Endocrine Tumours. Clin Endocrinol (Oxf). 2008;68(2):271-7. PubMed PMID: 17803708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. AU - Lindberg,Daniel, AU - Akerström,Göran, AU - Westin,Gunnar, Y1 - 2007/09/04/ PY - 2007/9/7/pubmed PY - 2012/4/25/medline PY - 2007/9/7/entrez SP - 271 EP - 7 JF - Clinical endocrinology JO - Clin Endocrinol (Oxf) VL - 68 IS - 2 N2 - OBJECTIVE: Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene at 11q13, enhances transcription of the cyclin-dependent kinase inhibitors (CDIs), CDKN2C (p18) and CDKN1B (p27) in mouse pancreatic islets, and inactivation of menin reduced CDKN2B (p15) expression in this mouse model. Here, we have compared the relative mRNA expression level and CpG methylation status of p18, p27 and p15 in 18 pancreatic endocrine tumours (PETs) with or without MEN1 gene mutations. DESIGN: Real-time quantitative PCR, DNA sequencing and pyrosequencing methylation analysis were employed. RESULTS: The p18 gene was expressed in 15 out of the 18 analysed PETs. The expression level was within the range of the normal pancreatic tissues or higher. Of the three remaining tumours with no expression, two displayed loss of heterozygocity (LOH) at 11q13, one derived from a MEN1 patient. The p27 gene was expressed in all PETs at a level higher than the normal pancreatic tissues, except for one tumour. Promoter methylation was not detected for p18 and p27. p15 expression was undetectable in 8/18 (44%) of the PETs, and no general relations to tumour syndrome, malignancy or MEN1 gene mutations were evident. This was not due to homozygous gene deletions, but the p15 promoter was hypermethylated in two insulinomas. No mutations were found in the p15 gene. CONCLUSIONS: Expression of p15, p18 and p27 was not generally related to the MEN1 gene mutational status of the investigated 18 PETs. The p15 gene was silenced by promoter hypermethylation in two tumours. Dysregulation of menin and the CDIs are important in PET tumorigenesis, and their interrelations remain to be elucidated. SN - 1365-2265 UR - https://www.unboundmedicine.com/medline/citation/17803708/Evaluation_of_CDKN2C/p18_CDKN1B/p27_and_CDKN2B/p15_mRNA_expression_and_CpG_methylation_status_in_sporadic_and_MEN1_associated_pancreatic_endocrine_tumours_ L2 - https://doi.org/10.1111/j.1365-2265.2007.03034.x DB - PRIME DP - Unbound Medicine ER -