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

Mei, Mei; Deng, Dajun; Liu, Tonghua; Sang, Xinting; Lü, Xin; Xiang, Hongding; Zhou, Jing; Wu, Haiyan; Yang, Yiying; Chen, Jie; Chen, Lu; Chen, Yuan‐Jia

doi:10.1210/jc.2009-0173

Cited by 49 publications

(35 citation statements)

References 37 publications

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“…In contrast to small intestinal NETs, high levels of microsatellite instability have been reported in two studies of pNET, and this has been associated with the inactivation of the mutL homologue 1 (MLH1) gene (Mei et al 2009). Methylation profiles of NETs of pancreatic and intestinal origin are also different (Chan et al 2003).…”

Section: Genome Instability and Mutationmentioning

confidence: 99%

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Walenkamp¹,

Crespo²,

Maya³

et al. 2014

Endocrine-Related Cancer

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In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.

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Section: Genome Instability and Mutationmentioning

confidence: 99%

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Walenkamp¹,

Crespo²,

Maya³

et al. 2014

Endocrine-Related Cancer

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“…11 Recently, promoter reporter assays showed that the A allele of this SNP conferred reduced transcriptional activity compared with the G allele, consistent with the notion that this allele might predispose to promoter methylation. 12 The potential role for genetic-based variants in conferring susceptibility of MLH1 to epigenetic silencing thus remains in question.…”

mentioning

confidence: 99%

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

et al. 2011

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Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP þ ), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93G4A SNP within the MLH1 promoter, CIMP þ and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of Z3 of five 3p22 genes with CIMP þ and the BRAF V600E mutation (Po0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP þ and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP þ provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.

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“…As this mutation site is a microsatellite region where errors tend to occur during DNA replication, mutations due to MMR abnormality are likely to occur. Recently, it has been shown that MMR gene abnormality is associated with pNET pathogenesis and proliferation [13]. Therefore, since MEN1 gene may be a target gene of MMR abnormality, it is necessary to further investigate the association between MEN1 gene and MMR gene abnormality.…”

Section: Discussionmentioning

confidence: 99%

“…Lynch syndrome is involved in the development of various tumors at an early age [11], and the accumulation of genetic mutations due to the abnormality in the MMR mechanism results in the pathogenesis of colorectal, endometrial, ovarian, stomach, pancreatic, ureter, renal pelvis, hepatobiliary tract and central nervous system cancers (glioblastoma), among others [12]. In addition, MMR gene expression has been studied in pancreas neuroendocrine tumors (pNETs) and is suggested to play a role in pNET pathogenesis and proliferation [13].…”

Section: Whole Genome Sequencing and Sanger Sequencing Analysismentioning

confidence: 99%

Atypical pituitary adenoma with MEN1 somatic mutation associated with abnormalities of DNA mismatch repair genes; MLH1 germline mutation and MSH6 somatic mutation

et al. 2017

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

Abstract: 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.

Cited by 49 publications

References 37 publications

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

Atypical pituitary adenoma with <i>MEN1</i> somatic mutation associated with abnormalities of DNA mismatch repair genes; <i>MLH1</i> germline mutation and <i>MSH6</i> somatic mutation

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