Microsatellite Instability and Mutations in DNA Mismatch Repair Genes in Sporadic Colorectal Cancers

Jeong, Seung‐Yong; Shin, Kihyuk; Shin, Joo‐Ho; Ku, Ja‐Lok; Shin, Yongho; Park, So‐Yeon; Kim, Woo Ho; Park, Jae-Gahb

doi:10.1007/s10350-004-7282-x

Cited by 51 publications

(33 citation statements)

References 38 publications

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“…Disease recurrence was detected by sonographic ultrasound, computed tomography, or magnetic resonance imaging, and was confirmed by pathologic examination. The microsatellite instability status of 230 of the enrolled cases had been previously reported (15); two cases were additionally analyzed for microsatellite instability at the BAT-25 and BAT-26 markers as previously described (15).…”

Section: Methodsmentioning

confidence: 99%

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Chang

Yoo

Lim

et al. 2005

Clinical Cancer Research

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114

109

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Purpose: Metabotropic glutamate receptors (mGluR) play a variety of roles in both neuronal and nonneuronal cells. Recently, we reported that mGluR4 mediates 5-fluorouracil resistance in a human colon cancer cell line. In this study, we evaluated the nonneural expression of mGluR4 and clarified the existence of mGluR4 in normal colon epithelium and colorectal carcinomas. We also investigated the association of mGluR4 expression levels with various clinicopathologic parameters. Experimental Design: mGluR4 expression was investigated in 21 normal and 312 malignant tissues from various organs using immunohistochemistry. In addition, 241 cases of colorectal carcinomas were examined and correlations between mGluR4 expression and various clinicopathologic parameters were then statistically analyzed. Results: Expression of mGluR4 was identified in the normal epithelia of the upper respiratory tract, gastrointestinal tracts, breast, uterine cervix, urinary bladder, and skin, whereas it was not detected in the thyroid, lung alveoli, liver, testis, or prostate. In the corresponding malignant tissues, mGluR4 expression was frequently identified in colorectal carcinoma (68%), followed by malignant melanoma, laryngeal carcinoma, and breast carcinomas. Expression of mGluR4 was detected in131 (54%) of 241colorectal carcinomas and12 (5%) cases among them showed overexpression in their cytoplasms. Loss of mGluR4 expression was negatively associated with tumor differentiation (P = 0.028), whereas overexpression of mGluR4 was positively associated with recurrence (P = 0.034) and poor disease-free survival (P = 0.017) in multivariate analyses. Conclusions: Our results suggest that mGluR4 signaling may play a role in colorectal carcinomas and that overexpression of mGluR4 is associated with poor prognosis.

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Section: Methodsmentioning

confidence: 99%

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Chang

Yoo

Lim

et al. 2005

Clinical Cancer Research

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114

109

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“…We have shown here that only 17% of tumors were MSI-H, an incidence similar to the 12 to 18% prevalence in sporadic colorectal cancer (3,22) and significantly lower than reported in HNPCC and patients with suspected HNPCC (5,23,24). BAT26 was used as the basis of a study on a limited assay that showed MSI-H rate as 9% in the 230 unselected cases of Korean sporadic colorectal cancer (25). Approximately 70% of 24 markers in our study accurately identified MSI-H, indicating that these markers could be applied to identifying these tumors.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Kim¹,

Lee²,

Ka³

et al. 2004

Clinical Cancer Research

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Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria.Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2).Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P ‫؍‬ 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P ‫؍‬ 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors.Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

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“…However, the rate of MSI-H in Korean endometrial cancer patients is higher than the 9.3% reported in primary sporadic CRC in Korea, 17 and similarly, our finding that 23% of endometrial tumor samples showed loss of MMR protein expression indicates that this rate is higher than the 8.6% seen in primary sporadic CRC in Korean patients. 18 We performed mutational analyses of patient samples from the identified clinical HNPCC, s-HNPCC and selected patients who showed both MSI-H and loss of MMR protein expression. Overall, the mutation rate in clinical HNPCC patients was 50% (2/4), and that in the s-HNPCC patients was 12.5% (1/8).…”

Section: Discussionmentioning

confidence: 99%

Hereditary nonpolyposis colorectal cancer in endometrial cancer patients

Yoon

Shin

et al. 2007

Intl Journal of Cancer

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Endometrial cancer is the second most common cancer in hereditary nonpolyposis colorectal cancer (HNPCC). It has often been overlooked to explore the possibility of HNPCC in endometrial cancer patients. Our study was to investigate how many HNPCC patients existed among endometrial cancer patients. Among patients who underwent hysterectomy for endometrial cancer at Seoul National University Hospital from 1996 to 2004, 113 patients were included, whose family history and clinical data could be obtained and tumor specimens were available for microsatellite instability (MSI) testing and immunohistochemical (IHC) staining of MLH1, MSH2 and MSH6 proteins. There were 4 (3.5%) clinical HNPCC patients fulfilling the Amsterdam criteria II, and 2 (2/ 4, 50%) of them carried MSH2 germline mutations. There were also 8 (7.1%) suspected HNPCC (s-HNPCC) patients fulfilling the revised criteria for s-HNPCC, and one (1/8, 12.5%) of them revealed MLH1 germline mutation. In 101 patients, who were not clinical HNPCC or s-HNPCC, 11 patients showed both MSI-high and loss of expression of MLH1, MSH2 or MSH6 proteins, and 2 (2/11, 18.2%) of them showed MSH6 germline mutations. In 113 patients with endometrial cancer, we could find 5 (4.4%) HNPCC patients with MMR germline mutation and 2 (1.8%) clinical HNPCC patients without identified MMR gene mutation. Family history was critical in detecting 3 HNPCC patients with MMR germline mutation, and MSI testing with IHC staining for MLH1, MSH2 and MSH6 proteins was needed in the diagnosis of 2 HNPCC patients who were not clinical HNPCC or s-HNPCC, especially for MSH6 germline mutation. ' 2007 Wiley-Liss, Inc.Key words: endometrial cancer; hereditary nonpolyposis colorectal cancer (HNPCC); microsatellite instability (MSI); mismatch repair gene (MMR); MLH1; MSH2; MSH6The incidence of endometrial cancer has been increasing significantly among general population in Korea over the past decades. 1 According to data on cancer incidence between 1999 and 2001 from the Korea Central Cancer Registry, the crude incidence rate per year is 3.11 cases per 100,000 Korean females.2 In a total of 43,627 new cases of female cancer registered by the Korea Central Cancer Registry in 2002, 825 cases were endometrial cancers, accounting for 1.9% of all malignancies in female. 3Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease characterized by high incidence of colorectal cancer (CRC), endometrial cancer and/or a variety of other cancers. 4 Defective DNA mismatch repair (MMR) process is caused by germline mutations in the MMR genes, leading to the development of HNPCC. Germline mutations have been identified in five of these genes, MSH2, MLH1, PMS1, PMS2 and MSH6, and mutations in MSH2, MLH1 and MSH6 appear to account for the MMR defects seen in the majority of HNPCC families. 5Endometrial cancer is the second most common cancer found in HNPCC families. 6 The lifetime risk of endometrial cancer for women with HNPCC is reported 40-60%, which is the same or greater than that o...

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Microsatellite Instability and Mutations in DNA Mismatch Repair Genes in Sporadic Colorectal Cancers

Abstract: The results indicated that a germline mutation of DNA mismatch repair gene was a rare event in sporadic colorectal cancers.

Cited by 51 publications

References 38 publications

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Hereditary nonpolyposis colorectal cancer in endometrial cancer patients

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