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

Departments of Gastroenterology (M.M., H.W., Y.Y., C.-M.L., Y.-J.C.), Pathology (T.-H.L., J.C.), and Surgery (X.-T.S., X.L.) and Key Laboratory of Endocrinology (Ministry of Health) (H.-D.X., Y.-J.C.), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences; and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) (D.D., J.Z.), Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital/Institute, Beijing 100730, People’s Republic of China

Address all correspondence and requests for reprints to: Dr. Yuan-Jia Chen, Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China. E-mail: yuanjchen{at}gmail.com or yuanjchen{at}yahoo.com.

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 x 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.