Research progress of MSI colorectal cancer / 实用肿瘤学杂志

Colorectal cancer is one of the most common malignant tumors,with the improvement of living standards and eating habits of Westernization.The incidence and mortality of colorectal cancer are on the rise in China.The development of colorectal cancer is a multi-step,multi-gene involved in the process.At present,chromosome instability(CIN)and microsatellite instability(MSI)are considered to be the main genetic pathways in colorectal cancer.This article reviews research progress of MSI colorectal cancer in clinical pathology and molecular characteristics.

p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Hypermethylation of the CpG island of p16(INK4a) occurs in a significant proportion of colorectal cancer (CRC). We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), and cetuximab. MATERIALS AND METHODS: Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci (p16, p14, MINT1, MINT2, MINT31, and hMLH1) in DNA extracted from formalin-fixed paraffin-embedded specimens. Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype (CIMP) markers including p16 and clinical outcome. RESULTS: Hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) and showed significant association with KRAS mutation (Fisher exact, p=0.01) and CIMP positivity (Fisher exact, p=0.002). Patients with p16-unmethylated tumors had significantly longer time to progression (TTP; median, 9.0 months vs. 3.5 months; log-rank, p=0.001) and overall survival (median, 44.9 months vs. 16.4 months; log-rank, p=0.008) than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy (n=6) had markedly shortened TTP (median, 2.8 months) compared to those with either KRAS or p16 aberrancy (n=11; median, 8.6 months; p=0.021) or those with neither (n=32; median, 9.0 months; p < 0.0001). In multivariate analysis, KRAS mutation and p16 methylation showed independent association with shorter TTP (KRAS mutation: hazard ratio [HR], 3.21; p=0.017; p16 methylation: HR, 2.97; p=0.027). CONCLUSION: Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI, irrespective of KRAS mutation.

Advances of CpG island methylation phenotypes in gastric cancer / 国际肿瘤学杂志

CpG island methylator phenotype (CIMP) refers to a set of multiple gene promoter CpG island methylation phenotype which exists in tumor at the same time.Many studies show that CIMP is ubiquitous in gastric cancer,which is related to the pathogenesis,diagnosis,patient's condition,prognosis and curative effect of gastric cancer.

Occurrence of CpG island methylation phenotype and expression of p27 in insulinoma / 中华胰腺病杂志

ObjectiveTo study the expression of p27 and its relationship with CpG island methylation phenotype (CIMP) in insulinoma.MethodsExpression of p27 was tested in 27 insulinoma tissues and 11 paired control tissues by immunohistochemistry staining.CpG island methylation of p16,MLH1,RAR-β,MGMT,THBS1 (CIMP) was detected in 27 insulinoma tissues and 11 paired cantrol tissues by methylation specific PCR (MSP).The data of p27 and CIMP expression were correlated with the clinicopathological characteristics.ResultsThe positive expression rate of p27 in insulinoma tissues was significantly lower than that in paired control tissues (48％ vs 91％,P =0.008).High rate of CIMP occurrence in insulinoma tissues was 33％ (9/27),while it was 18％ (2/11) in paired control tissues,and difference between the two groups was not statistically significant ( P =0.350 ).The methylation of MGMT was reversely associated with p16 methylation ( P =0.004).p27 expression in insulinoma tissues was reversely associated high rate of CIMP occurrence but it was not statistically significant ( P =0.420).Neither the expression of p27 nor the occurrence of CIMP was associated with the clinicopathological features.ConclusionsDown-regulation of p27 and high rate of CIMP occurred in insulinomas,suggesting that the inactivation of p27 and epigenetic alterations of several genes might contribute to the carcinogenesis of insulinoma.

Promoter Methylation in the Genesis of Gastrointestinal Cancer

Colorectal cancers (CRC)-and probably all cancers-are caused by alterations in genes. This includes activation of oncogenes and inactivation of tumor suppressor genes (TSGs). There are many ways to achieve these alterations. Oncogenes are frequently activated by point mutation, gene amplification, or changes in the promoter (typically caused by chromosomal rearrangements). TSGs are typically inactivated by mutation, deletion, or promoter methylation, which silences gene expression. About 15% of CRC is associated with loss of the DNA mismatch repair system, and the resulting CRCs have a unique phenotype that is called microsatellite instability, or MSI. This paper reviews the types of genetic alterations that can be found in CRCs and hepatocellular carcinoma (HCC), and focuses upon the epigenetic alterations that result in promoter methylation and the CpG island methylator phenotype (CIMP). The challenge facing CRC research and clinical care at this time is to deal with the heterogeneity and complexity of these genetic and epigenetic alterations, and to use this information to direct rational prevention and treatment strategies.

DNA Methylation of Multiple Genes in Gastric Cancer: Association with CpG Island Methylator Phenotype and Helicobacter pylori Infection

PURPOSE: Methylation of gene regulatory elements plays an important role in gene inactivation without genetic alteration. Gastric cancer is one of the tumors that exhibit a high frequency of CpG island hypermethylation. The purpose of this study was to investigate the occurrence of CpG island hypermethylation in gastric carcinoma in relation to H. pylori infection, CIMP and clinicopathologic variables. MATERIALS AND METHODS: We investigated the promoter methylation status of six genes (hMLH1, p16, p14, COX-2, MGMT, E-cadherin) and CIMP in 36 gastric carcinoma tissues as well as in nontumor tissues. CIMP status was investigated by examining the methylation status of MINT 1, 2, 12, 25 and 31. The methylation status of the promoter was examined by methylation-specific PCR (MSP) and H. pylori infection was examined by histological diagnosis after staining with Warthin-Starry silver. RESULTS: Among the 36 gastric carcinoma tissues, DNA hypermethylation was detected in the following frequencies: 14 (38.9%) for p14, 13 (36.1%) for p16, 8 (22.2%) for MGMT, 10 (27.8%) for COX-2, 21 (58.3%) for E-cadherin, and 6 (16.7%) for hMLH1. The frequencies for MINT1 and MINT25 hypermethylation were significantly higher in tumor tissues than in nontumor tissues. 16 (44.4%) of the 36 gastric carcinoma tissues were positive for the CIMP. CIMP-H tumors were associated with older patients and larger tumor size than CIMP-L tumors. We found a significant association between the presence of the CIMP and hypermethylation of p16. Hypermethylation of p16 and MINT2 were significantly different when compared by age. MINT1 gene methylation was significantly associated with H. pylori infection (P=0.004). CONCLUSION: Our results suggest that aberrant hypermethylation of multiple tumor related genes (hMLH1, p16, p14, COX-2, MGMT, E-cadherin, MINT1, 2, 12, 25, 31) occurs frequently in gastric carcinoma tissues. The hypermethylation of MINT1 was significantly higher in the tumor tissues and was associated with H. pylori infection.

A Clinical Analysis of Methylation Status of Tumor Suppressor Genes in Breast Cancer

PURPOSE: Aberrant methylation of CpG islands in gene promoters has been considered as a common mechanism for suppressing gene expression in cells. Hypermethylation of CpG islands in promoters is associated with silencing of transcription in various tumor suppressor genes and recent studies identified a CpG island methylator phenotype (CIMP) suggesting common methylation defect in cancer cells. For breast cancer, several genes were previously reported to be hypermethylated, but it is unclear whether the CIMP status is associated with any clinicopathological characteristics of breast cancer. In this study, we investigated the methylation patterns of several genes such as p16(INK4a), O(6)-methyguanine-DNA methyltransferase (MGMT), Death associated protein kinase (DAPK), E-cadherin, hMLH1, and four loci such as Methylation in tumor (MINT: MINT1, MINT2, MINT25, MINT31) and analyzed the correlation with clinical features. METHODS: 85 patients who underwent curative surgery for breast cancer were studied retrospectively using their paraffin-embedded tissues and medical records. Immunohistochemical staining were performed according to their hormone receptors. DNA extraction, sodium bisulfite modification and methylation specific PCR (MSP-PCR) were performed with some modifications. RESULTS: The rates of E-cadherin and MINT 31 methylation in cancer tissue were significantly higher than those of normal tissues (P<0.05). There was no statistical correlation between methylation status of each suppressor genes and hormone receptor except DAPK methylation with progesteron receptor. The rate of E-cadherin methylation was significantly high in stage II (P=0.010). For 5-year survival and disease-free survival rate, the group with methylated MINT1 and MINT25 had significantly better outcome than unmethylated group (P<0.05). There was no statistical significance between CIMP status and other prognostic factors such as hormone receptor and stage (P=0.885). But, CIMP-High group was significantly lower than CIMP-Low group in 5-year survival (P=0.001) and disease-free survival rate (P=0.024). CONCLUSION: The methylation of E-cadherin and some MINT loci seems closely related to tumorigenesis in breast cancer and CIMP status have some value as a prognostic indicator after surgery in breast cancer but more large scale study will be needed.

Cancer Epigenetics / 대한소화기학회지

Knowledge regarding molecular events of cancer development has been rapidly accumulated during the last decade. The discovery of tumor suppressor gene-silencing by aberrant promoter CpG island hypermethylation and histone-directed chromatin remodeling has led epigenetics to its recognition as an important alternative mechanism for carcinogenesis. Epigenetics does not involve changes in nucleotide sequences, but it affects on genetic composition in many ways. Cancer cells integratively co-opt genetic and epigenetic mechanisms to acquire different aspects of carcinogenetic phenotypes. Since epigenetic changes can be reversed with relative ease, the research of cancer epigenetics provides great potential for new therapeutic regimens.