Clinical Implications of Microsatellite Instability and MLH1 Gene Inactivation in Sporadic Insulinomas

Context: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. Objective: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch...

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Published in:The journal of clinical endocrinology and metabolism 2009-09, Vol.94 (9), p.3448-3457
Main Authors: Mei, Mei, Deng, Dajun, Liu, Tong-Hua, Sang, Xin-Ting, Lu, Xin, Xiang, Hong-Ding, Zhou, Jing, Wu, HaiYan, Yang, YingMai, Chen, Jie, Lu, Chong-Mei, Chen, Yuan-Jia
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - analysis
Adaptor Proteins, Signal Transducing - genetics
Adolescent
Adult
Aged
Biological and medical sciences
DNA Methylation
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Exons
Feeding. Feeding behavior
Female
Fundamental and applied biological sciences. Psychology
Humans
Insulinoma - genetics
Insulinoma - pathology
Loss of Heterozygosity
Male
Medical sciences
Microsatellite Instability
Middle Aged
Mutation
MutL Protein Homolog 1
MutS Homolog 2 Protein - analysis
Nuclear Proteins - analysis
Nuclear Proteins - genetics
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Tumors. Hypoglycemia
Vertebrates: anatomy and physiology, studies on body, several organs or systems
Vertebrates: endocrinology
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Summary:Context: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. Objective: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. Design and Patients: We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. Results: A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 × 10−6, respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). Conclusion: High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients. Detecting of a high rate of microsatellite instability can be used to distinguish malignancy from benign, and predict clinical outcome of the sporadic insulinomas.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2009-0173