• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8027-8034
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• 2014

Genetic instability contributes to the development and progression of gastric cancer, one of the leading causes of cancer death worldwide. Microsatellite instability (MSI) has been hypothesized to be involved in carcinogenesis, althgough its mechanisms and exact roles in gastric cancer remain largely unknown. Our aim was to identify associated clinicopathological characteristics and prognostic value of MSI in gastric cancer and precancerous lesions including gastritis, metaplasia, dysplasia, and adenoma. Because mitochondrial DNA has a different genetic system from nuclear DNA, the results of both nuclear MSI and mitochondrial MSI in gastric cancer were reviewed. This review provides evidence that genetic instability of nuclear and mitochondrial DNAs contributes to early stages of gastric carcinogenesis and suggests possible roles in predicting prognosis.

• Korean Journal of Clinical Laboratory Science
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• v.46 no.2
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• pp.59-63
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• 2014

The death toll of Colorectal Carcinoma in Korea was 1,826 and 7,721 in the years 1992 and 2011, respectively. This rate of increase was shown to be more than 4.23 times higher than that of any other form of cancer. Therefore, Colorectal Carcinoma requires various diagnostic methods, and Microsatellite Instability (MSI) was applied as a new diagnostic tool. From this study with several microsatellite markers, only marker #13 was detected and observed D13S160 13% (4/30), D13S292 13% (4/30), D13S153 10% (3/30) in order. From the results of amplication with microsatellite marker, D13S292 37% (11/30), D13S153 33% (10/30), D13S160 33% (10/30) in order were shown. The appearance of a genetic mutation, which depends on the loci of Colorectal Carcinoma, was shown amplication from rectal cancer (3.77) which was higher than that of right Colorectal Carcinoma (2.08) (p<0.018). The genetic mutation with lymph node (4.13) appeared higher than normal (1.93) (p<0.001). There were no great differences in the genetic mutation dependent on disease, histological classification and increased group of serum CEA. Accordingly, it is suggested that the correct primers, which can evaluate MSI well from colorectal carcinoma, should be chosen and that MSI be considered a good prognosis and quality control tool.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.26 no.4
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• pp.337-344
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• 2000

Germ-line mutations at DNA repair loci confer susceptibility to colon cancer in hereditary non-polypopsis colorectal cancer. Somatic loss of DNA mismatch repair gene has been reported in a large variety of other tumor types. Replication errors(RERs) judged by microsatellite instability(MSI) and its associated mutations have been recognized as an important mechanism in various tumor types. To investigate associations between MSI and oral squamous cell carcinoma, the frequency of MSI using 12 microsatellite markers were analyzed for the series of oral tumors. Of 17 tumors, 8 cases(47%) did not show instability at any of the 12 loci; 5(29%) showed instability at $2{\sim}3$ loci; and 4(24%) showed instability above 4 loci. The 4 cases showing widespread MSI did not differ from those without evidence of instability in terms of age at diagnosis, degree of differentiation, metastasis to lymph node, tumor location or the presence of mutations in the p53 tumor suppressor gene. DCC and D17S 796 were the most frequently detected in MSI analysis. There were no correlation between smoking and MSI frequency, instead, smoking was suggested to increase the mutation rate of p53 and development of oral carcinomas.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2587-2592
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• 2016

Background: Early onset sporadic colorectal cancer (CRC) is a biologically and clinically distinct entity hypothesized to exhibit differences in histological features and microsatellite instability (MSI) as compared to typical onset CRC. This study compared the MSI status, mismatch repair enzyme deficiency and clinicopathological features of early onset (aged ${\leq}45$ years) with controls (>45 years). Materials and Methods: A total of 30 cases and 30 controls were analyzed for MSI status using the Bethesda marker panel. Using antibodies against hMLH1, hMSH2 and hMSH6, mismatch repair protein expression was assessed by immunohistochemistry. Molecular characteristics were correlated with clinicopathological features. Results: The early onset sporadic CRCs were significantly more poorly differentiated tumors, with higher N2 nodal involvement and greater frequency of signet ring phenotype than the typical onset cases. MSI was observed in 18/30 cases, with 12/18 designated as MSI-high (MSI-H) and 6/18 designated as MSI-low (MSI-L). In the control group, 14 patients exhibited MSI, with 7 MSI-H and 7 MSI-L. MSI tumors in both cases and controls exhibited loss of hMLH1, hMSH2 and hMSH6. MSS tumors did not exhibit loss of expression of MMR proteins, except hMLH1 protein in 3 controls. No statistically significant difference was noted in MSI status or expression of MMR proteins in cases versus controls. Conclusions: Microsatellite status is comparable between early and typical onset sporadic CRC patients in Pakistan suggesting that differences in clinicopathological features between these two subsets are attributable to other molecular mechanisms.

• Korean Journal of Clinical Oncology
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• v.9 no.2
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• pp.80-86
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• 2013

Purpose: Hypermethylation of human mut L homologue 1 (hMLH1) promoter region is known to cause sporadic microsatellite instability (MSI) colorectal cancers. 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in folate metabolism, acting as a methyl donor for DNA methylation. In this study, we investigate whether the polymorphism of MTHFR 677C>T plays a role in the alteration of the promoter-specific hypermethylation, predisposing to MSI colorectal cancers. Methods: Total of 487 sporadic colorectal cancer patients in CHA Bundang Medical Center were collected. MSI was identified when two or more are positive among five microsatellite markers (BAT25, BAT26, D17S250, D5S346, D2S123). The others were classified as microsatellite stable (MSS). Polymorphism of MTHFR 677C>T was genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: MSI was observed in 65 of 487 patients (12.73%). MSI colorectal cancers showed similar clinicopathological features with previously reported; younger age onset, right-sided preponderance, mucinous and poorly differentiated histology, lower stage, fewer lymph node metastases than MSS tumors (each P<0.05). The frequency of MTHFR 677TT genotype was 17.7% in the MSI group higher than 14.6% in the MSS group (P=0.17). Although not statistically significant, compared to the MTHFR 677CC referent, MTHFR 677 CT+TT genotype was more likely to have MSI than MSS (odds ratio, 1.81; 95% confidence interval, 0.94 to 3.68; P=0.06). Conclusion: This study demonstrated higher frequency of MTHFR 677TT genotype in MSI colorectal cancers. Furthermore, individuals with MTHFR 677CT+TT variant type might potentially develop MSI rather than MSS colorectal cancers.

• Journal of Gastric Cancer
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• v.3 no.1
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• pp.50-55
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• 2003

Background: An aberrant function of the mismatch repair system has been reported to underlie carcinogenesis in several tumors, including colorectal and gastric carcinomas, and to induce the typical genotype of microsatellite instability (MSI). Purpose: We aimed to determine the frequency of MSI in early-onset sporadic gastric carcinoma and elucidate the role of promoter methylation in hMLH1 as the mechanism of MSI. Materials and Methods: Thirty-six early-onset sporadic gastric carcinomas were analyzed to determine the status of MSI and the frequency of methylation of the promoter region in hMLH1. MSI was determined using five markers recommended by NCI: MSI-H (high), MSI-L (low), and MSS (Microsatellite stable). Methylation specific PCR (MSP) and direct automated genomic sequencing analysis with DNA modified by sodium bisulfite have been performed to confirm promoter region methylation. All the data were analyzed regarding characteristics of molecular changes, and clinicopathologic variables. Results: The microsatellite status was determined as MSI-H in five cases ($13.8\%$), MSI-L in 13 cases ($36.1\%$), and MSS in 18 cases ($50.0\%$). hMLH1 was methylated in seven cases ($19.4\%$). In all cases of MSI-H, promoter of hMLH1 was methylated, and in two of the 13 cases of MSI-L, hMLH1 promoter methylation was identified. Methylation was not found in any cases of MSS. Promoter methylation in hMLH1 was significantly correlated with MSI status (P<0.001). We could not find any relationship between MSI and clinicopathologic parameters. Conclusion: These results suggest that an abnormal function of the mismatch repair system may be associated with gastric carcinogenesis in more than $10\%$ of early-onset gastric carcinomas and MSI appeared to be closely related to the promoter methylation in hMLH1.

• Journal of Gastric Cancer
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• v.8 no.4
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• pp.169-175
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• 2008

Purpose: The main target of 5-fluorouracil (5-FU) is thymidylate synthase (TS). A high TS expression has been identified as promoting resistance to 5-FU. For colorectal cancers, the response to 5-FU based adjuvant chemotherapy is different according to the microsatellite instability (MSI) status. The reports on the relationship between MSI and the TS expression in colorectal cancer have been inconsistent. No data is available for gastric cancer regarding the relationship between MSI and the TS expression. Therefore, we studied the relationship between MSI and the TS expression in gastric cancer. Materials and Methods: Ninety-nine consecutive patients who underwent radical gastrectomy for gastric cancer from January 2004 to May 2006 at Bundang CHA hospital were studied. MSI was assessed for five markers (BAT25, BAT26, D2S123, D5S346, and D17S250) by PCR and with using an ABI prism 3100 Genetic analyzer. The TS expression was analyzed by immunohistochemistry with using mouse anti-thymidylate synthase monoclonal antibody to the TS 106 clone. Results: Out of the ninety-nine patients, MSS/MSI-L was detected in 92 (92.1%) cases and 7 cases (7.1%) were MSI-H. A negative TS expression was found in 46 (46.5%) cases, a low TS expression was found in 33 (33.3%) and a high TS expression was found in 20 (20.2%). Out of 92 MSS/MSI-L patients, the number of patients with negative, low and high TS expressions were 46 (50%), 30 (32.6%) and 16 (17.4%), respectively. Out of the 7 MSI-H patients, the number of patients with negative, low and high TS expressions were 0 (0%), 3 (42.9%) and 4 (57.1%), respectively. The relationship between MSI-H and a high TS expression was statistically significant. Conclusion: Gastric cancer with MSI-H showed higher levels of a TS expression compared to the gastric cancer with MSS/MSI-L.

• Journal of Gastric Cancer
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• v.19 no.4
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• pp.427-437
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• 2019

Purpose: We aimed to evaluate the clinical characteristics of microsatellite instability in early gastric cancer. Materials and Methods: The microsatellite instability status of resected early gastric tumors was evaluated using two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide repeat markers (D5S346, D2S123, and D17S250). Tumors with instability in two or more markers were defined as microsatellite instability-high (MSI-H) and others were classified as microsatellite stable (MSS). Results: Overall, 1,156 tumors were included in the analysis, with 85 (7.4%) classified as MSI-H compared with MSS tumors. For MSI-H tumors, there was a significant correlation with the female sex, older age, tumor location in the lower gastric body, intestinal histology, lymphovascular invasion (LVI), and submucosal invasion (P<0.05). There was also a trend toward an association with lymph node (LN) metastasis (P=0.056). In mucosal gastric cancer, there was no significant difference in MSI status in tumors with LN metastasis or tumors with LVI. In submucosal gastric cancer, LVI was more frequently observed in MSI-H than in MSS tumors (38.9% vs. 25.0%, P=0.027), but there was no difference in the presence of LN metastases. The prognosis of MSI-H tumors was similar to that of MSS tumors (log-rank test, P=0.797, the hazard ratio for MSI-H was adjusted by age, sex, pT stage, and the number of metastatic LNs, 0.932; 95% confidence interval, 0.423-2.054; P=0.861). Conclusions: MSI status was not useful in predicting prognosis in early gastric cancer. However, the frequent presence of LVI in early MSI-H gastric cancer may help guide the appropriate treatment for patients, such as endoscopic treatment or limited LN surgical dissection.

• Tuberculosis and Respiratory Diseases
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• v.48 no.1
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• pp.24-32
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• 2000

Purpose: Microsatellite instability(MSI) is frequently used as an indicator of microsatellite mutator phenotype(MMP) tumors. MSI has been observed in a percentage of non-small cell lung cancer(NSCLC). However, its role in tumorigenesis of NSCLC remains unknown. The frequency and pattern of MSI in NSCLC were evaluated and clinical parameters of MSI-positive tumors with those of MSS(microsatellite stable) tumors were compared. Materials and Methods: Twenty surgically resected NSCLCs were analyzed for 15 microsatellite markers located at chromosomes 3p and 9p. The peripheral blood lymphocytes of patients were used as the source of the normal DNA. Results: 1) Of 20 cases, 8(40%) demonstrated MSI. 2) Instability was observed more frequently in tri- and tetra-nucleotide repeats than in dinucleotide repeats. In all cases, instability appeared as a shift of individual allelic bands. 3) LDH was observed in 10(50%) of 20 tumors analyzed. 4) Of 20 cases, MSI-H tumor(showing MSI in the majority of markers) was absent. There were 5 MSI-L tumors(showing MSI in a greater than 10% of markers). 5) No significant difference was observed between MSI-L tumors and MSI-negative tumors in terms of clinicopathologic features such as pack-year history of smoking, histologic subtype, and(delete) stage of disease. There was also no significant difference in the incidence of LDH in relation to the status of MSI. Conclusion: These data strongly suggest that MSI plays different roles in lung and colon cancer. MMP pathway appears to be far less important in the tumorigenesis of NSCLC, caused mainly by cigarette smoke, with little familial tendency.

• Journal of Gastric Cancer
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• v.10 no.4
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• pp.149-154
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• 2010

Purpose: Replication error is an important mechanism in carcinogenesis. The microsatellite instability (MSI-H) of colorectal cancers is associated with the development of multiple cancers. The influence of MSI-H on the development of multiple gastric cancers in sporadic gastric cancer patients has not been defined. This study was performed to reveal the association between the clinicopathologic features and MSI in sporadic gastric cancers. Materials and Methods: Between July 2004 and March 2009, the clinicopathologic characteristics, including MSI status, were evaluated in 128 consecutive patients with sporadic gastric cancers. None of the patients had hereditary non-polyposis colorectal cancer of familial gastric cancer. The markers that were recommended by the NCI to determine the MSI status for colorectal cancers were used Results: MSI-H cancers were found in 10.9% of the patients (14/128). Synchronous gastric cancers were shown in 4 patients (3.1%). Synchronous cancers were found in 2 of 14 patients with MSI-H gastric cancer (14.3%) and 2 of 114 patients with MSS gastric cancer (1.8%; P=0.059, Fisher's exact test). Among the patients with synchronous cancer 50% (2/4) had MSI-H cancer, but 9.7% of the patients (12/124) without synchronous cancer had MSI-H cancer. MSI-H (RR, 24.7; 95% CI, 1.5~398.9; P=0.024) was related with to synchronous gastric cancer, but age, gender, family history, histologic type, location, gross morphology, size, and stage were not related to synchronous gastric cancer. Conclusions: MSI is associated with the intestinal-type gastric cancer and the presence of multiple gastric cancers in patients with sporadic gastric cancer. Special attention to the presence of synchronous and the development of metachronous multiple cancer in patients with MSI-H gastric cancer is needed.