Standardized approach for microsatellite instability detection in gastric carcinomas

Musulén, Eva; Reyes, Gerardo; Sancho, F J; Peinado, Miguel A.; Esteller, Manel; Herman, James G.; Combalía, Neus; Rey, M.; Capellà, Gabriel

doi:10.1016/j.humpath.2003.10.021

Cited by 11 publications

(8 citation statements)

References 21 publications

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“…( 35,36 ) The lower frequency of dMMR in mCRC is consistent with previous findings. ( 8,12,19,37,38 ) Among our 197 patients, both immunohistochemistry for hMLH1 and MSH2 and MSI PCR data were available for 123 patients. Only five (4.1%) cases showed MSI‐H, which were all dMMR tumors.…”

Section: Discussionmentioning

confidence: 99%

Association between deficient mismatch repair system and efficacy to irinotecan‐containing chemotherapy in metastatic colon cancer

Kim

Hong²,

Ryu³

et al. 2011

Cancer Science

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The present study investigated the association between deficient mismatch repair (dMMR) and efficacy outcomes of irinotecanbased first-line chemotherapy in patients with metastatic colorectal cancer (mCRC). Among 297 patients with sporadic mCRC receiving an irinotecan-containing regimen as first-line chemotherapy, 197 with available paraffin-embedded tissues were included in the current analysis. Tumors displaying loss of MMR protein (MLH1 or MSH2) and/or a microsatellite instability-high (MSI-H) genotype by PCR were classified as dMMR. Deficient mismatch repair was found in 23 evaluable tumors, among which eight displayed negativity for MLH1 expression, 11 for MSH2 expression, and four for both. The overall response rate was 47.2% (46.0% in proficient MMR (pMMR) and 56.5% in dMMR), with no significant difference between the two groups (P = 0.569). Median progression-free survival was 8.85 months in patients with dMMR tumors and 6.82 months in patients with pMMR tumors, but this difference did not reach statistical significance (P = 0.089). Median overall survival was not different between the two groups (P = 0.413). Efficacy outcomes of first-line irinotecan-based chemotherapy did not differ significantly between mCRC patients with pMMR and those with dMMR. Our data collectively indicate that MMR status is not effective as a single predictive marker for response to irinotecan-based chemotherapy in mCRC patients. (Cancer Sci 2011; 102: 1706-1711 C hemotherapy is the cornerstone treatment for metastatic colorectal cancer (mCRC). The median overall survival (OS) for mCRC patients has markedly improved in recent years with the application of a combination regimen comprising 5-fluorouracil (5-FU) with oxaliplatin or irinotecan, and moleculartargeted agents such as bevacizumab or cetuximab.(1) Despite these improvements, a significant proportion of patients do not respond to chemotherapy. Thus, predictive factors are needed to identify the specific patients that might benefit from this treatment.Colorectal cancer (CRC) develops through accumulating genetic changes. Deficient mismatch repair (dMMR), also termed microsatellite instability (MSI), is one of the genetic pathways.(2) Germline alterations of MMR genes, usually hMSH2 or hMLH1, cause susceptibility to Lynch syndrome, but dMMR is also observed in 10-20% of patients with sporadic CRC.(3) Colorectal cancer with dMMR displays several distinct pathological features, including location in the proximal colon, poor histological differentiation, a high number of tumor-infiltrating lymphocytes and, in many cases, mucinous type. Patients with dMMR tumors generally have better prognosis than those with proficient MMR (pMMR) tumors.(4-6) Several studies have investigated whether MSI is a prognostic factor and its potential predictive role regarding response to chemotherapy. Earlier studies reported excellent prognosis without treatment for approximately 20% stage II cancer patients with MSI-H, as well as apparent lack of benefit of 5-FU-based adjuvant therapy. (7,8) An o...

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Section: Discussionmentioning

confidence: 99%

Association between deficient mismatch repair system and efficacy to irinotecan‐containing chemotherapy in metastatic colon cancer

Kim

Hong²,

Ryu³

et al. 2011

Cancer Science

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“…There have been reports showing that the microsatellite instability phenotype is linked with promoter hypermethylation of hMLH1 and MGMT (27). Furthermore, many studies including with Korean patients showed that gastric cancer with microsatellite instability was associated with distal location (28-31).…”

Section: Discussionmentioning

confidence: 99%

DNA Hypermethylation of Tumor-Related Genes in Gastric Carcinoma

et al. 2005

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The hypermethylation of the CpG islands is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed the methylation status of genes for cell repair such as hMLH1, MGMT, and GSTP1, and a gastric cancer-specifically methylated DNA fragment, MINT 25 in gastric cancer cases and control groups. The study population consisted of 100 gastric cancer patients (50 distal and 50 proximal carcinomas), and 238 healthy controls. All genes showed more frequent hypermethylation in the cases than in the control group (p<0.0001). We investigated the association between promoter hypermethylation and relevant parameters including age, gender, alcohol consumption, smoking, and family history. There was a common hypermethylation of hMLH1 (p=0.008), MGMT (p=0.0001), and GSTP1 (p=0.0003) in females. This study also demonstrates that hypermethylation was strongly associated with non-drinkers (MGMT, p=0.046 and MINT 25, p=0.049) and non-smokers (hMLH1, p=0.044; MGMT, p=0.0003; MINT 25, p=0.029). Moreover, the frequency of MINT 25 hypermethylation increased with age (p=0.037), and MGMT methylation was frequently detected in distal gastric cancer than in proximal type (p=0.038). Our study suggested that promoter hypermethylation of the genes involved in cell repair system and MINT 25 is associated strongly with some subgroups of primary gastric carcinoma.

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“…Four studies assessed the association between MLH1 promoter methylation and GC in cancer vs. healthy blood samples, including 270 GC blood samples and 104 healthy blood samples [17, 53, 75, 83]. Forty-eight studies evaluated the relationship between MLH1 promoter methylation and the clinicopathological features of 3656 GC patients [15, 18, 19, 29-37, 39-48, 51, 52, 54-58, 60, 62-64, 66-70, 72, 73, 76-83]. Two studies reported the prognostic information on OS [53, 56].…”

Section: Resultsmentioning

confidence: 99%

“…Cancer-related genes, such as tumor suppressor genes (TSGs), or DNA repair genes are commonly methylated in the promoter regions of CpG islands, which leads to the dysfunction or loss of gene expression, cancer initiation and progression [84, 85]. The absence or downregulation of MLH1 gene expression via promoter methylation was reported in GC [15, 32-34, 36, 37, 39, 42, 44-46, 50, 56, 59, 60, 62, 64, 72, 76, 77]. MLH1 promoter methylation is detected in some cancers, such as bladder cancer [86], colorectal cancer [87] and GC [18].…”

Section: Discussionmentioning

confidence: 99%

“…observed an association between MLH1 promoter methylation and age, but other studies reported no correlation [19, 36, 40, 41, 47, 48, 55, 64, 66, 78, 82, 83]. Twenty studies reported that MLH1 promoter methylation significantly correlated with microsatellite status [15, 30, 33, 37, 39-46, 51, 52, 55, 56, 60, 62, 63, 79], but three studies demonstrated no association [57, 64, 76]. Our study revealed that MLH1 promoter methylation correlated with age and microsatellite status, and it was notably higher in patients 60 years of age or older than in patients younger than 60 years and higher in patients with MSI than in patients with MSS.…”

Section: Discussionmentioning

confidence: 99%

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Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

Hu¹,

Qin²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. Methods: The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. Results: A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis. MLH1 promoter methylation was significantly higher in GC samples than in gastric adenomas, chronic gastritis, adjacent tissues, normal gastric mucosa, and normal healthy blood samples, but it exhibited a similar frequency in GC vs. intestinal metaplasia and dysplasia samples. MLH1 promoter methylation correlated with age and microsatellite instability (MSI), but it was not associated with gender, H. pylori infection, smoking, drinking behaviors, pathological histology, tumor differentiation, clinical stage, lymph node status, distant metastasis, or overall survival of GC. MLH1 promoter methylation exhibited a poor sensitivity value (< 0.5) in patients with GC compared with adjacent tissues, gastric adenomas, chronic gastritis, normal gastric mucosa, and normal healthy blood samples. The pooled sensitivity, specificity, and AUC of MLH1 promoter methylation in GC with MSI vs. GC with microsatellite stability (MSS) samples were 0.64, 0.96, and 0.90, respectively. Conclusions: Our results suggest that the detection of MLH1 promoter methylation may be a potential prognostic biomarker for GC patients with MSI.

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Standardized approach for microsatellite instability detection in gastric carcinomas

Cited by 11 publications

References 21 publications

Association between deficient mismatch repair system and efficacy to irinotecan‐containing chemotherapy in metastatic colon cancer

Association between deficient mismatch repair system and efficacy to irinotecan‐containing chemotherapy in metastatic colon cancer

DNA Hypermethylation of Tumor-Related Genes in Gastric Carcinoma

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

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