• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.1995-1998
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• 2013

Objective: To study the expression of the mismatch repair proteins hMSH2 and nm23 in sporadic colorectal cancer, determine any inter-relationship, and further investigate any clinical significance. Methods: Expression of hMSH2 and nm23 proteins was assessed in 87 colorectal cancer tissues by SP immunohistochemistry, with analysis of survival using follow-up data. Results: In the sporadic colorectal cancer tissues, nm23 protein expression appeared independent of the histological type (P>0.05), but correlated with the invasion depth and lymphatic metastasis (P<0.05). In contrast, hMSH2 protein expression was not significantly correlated with these clinicopathologic features (P>0.05), although it positively correlated with that of nm23 protein in the sporadic colorectal cancers (rs=0.635, P<0.05). Combined expression of the two was found to be related with invasion depth, lymphatic metastasis and prognosis of sporadic colorectal cancer (P<0.05). Conclusion: nm23 protein level was related with the degree of malignancy, and could be used as an index to predict the invasion and metastasis potential. The expression of hMSH2 protein is positively correlated that of nm23 protein, and the combined expression of the two has certain guiding significance for the prognosis of sporadic colorectal cancer.

• Journal of Medicine and Life Science
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• v.15 no.2
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• pp.42-45
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• 2018

Colorectal cancer (CRC) is a third leading cause of cancer-related death in cancer patients. Sporadic and inflammation-related colon carcinogenesis are major mechanism of colorectal cancer. In vivo CRC models have been developed and implicated to understand their mechanisms upon a different type of CRC. Moreover, recently animal models have played important roles in chemopreventive and preclinical trials over the years. In this mini-review, the aim is to introduce various animal models of CRC and help the understanding to establish in vivo experimental plans according to the cancer type of CRC.

• 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.

• Journal of Genetic Medicine
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• v.7 no.1
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• pp.24-36
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• 2010

Colorectal cancer is one of the most steeply increasing malignancies in Korea. Among 398,824 new patients recorded by the Korea Central Cancer Registry between 2003 and 2005, 47,915 cases involved colorectal cancers, accounting for 12.0 % of all malignancies. In 2002, total number of colorectal cancer cases had accounted for 11.2 % of all malignancies. Hereditary syndromes are the source of approximately 5% to 15% of overall colorectal cancer cases. Hereditary colorectal cancers are divided into two types: hereditary nonpolyposis colorectal cancer (HNPCC), and cancers associated with hereditary colorectal polyposis, including familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, juvenile polyposis, and the recently reported hMutYH (MYH)-associated polyposis (MAP). Hereditary colorectal cancers have unique clinical features distinct from sporadic cancer because these are due to germline mutations of the causative genes; (i) early age-of-onset of cancer, (ii) frequent association with synchronous or metachronous tumors, (iii) frequent association with extracolonic manifestations. The management strategy for patients with hereditary colorectal cancer is quite different from that for sporadic cancer. Furthermore, screening, genetic counseling, and surveillance for at-risk familial member are also important. A well-organized registry can plays a central role in the surveillance and management of families affected by hereditary colorectal cancers. Here, we discuss each type of hereditary colorectal cancer, focusing on the clinical and genetic characteristics, management, genetic screening, and surveillance.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6403-6409
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• 2013

Purpose: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associated with colorectal neoplasms that display somatic $G:C{\rightarrow}T:A$ transversions. However, the effect of single germline variants has not been widely studied, prompting the present investigation of monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC) in a Chinese population. Patients and Methods: Between January 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donors were screened randomly for 7 potentially pathogenic germline MYH exons using genetic testing technology. Variants of heterozygosity at the MYH locus were assessed in both sporadic cancer patients and healthy controls. Univariate and multivariate analyses were performed to determine risk factors for cancer onset. Results: Five monoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which were detected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1 proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 $G{\rightarrow}A$, exon 1-292 $G{\rightarrow}A$ and intron 1+11 $C{\rightarrow}T$, being identified in 13 CRC patients and 2 normal blood donors. A variant of base replacement, intron 10-2 $A{\rightarrow}G$, was identified in the exon 10 region in 21 cases and 7 controls, while a similar type of variant in the exon 13 region, intron 13+12 $C{\rightarrow}T$, was identified in 8 cases and 6 controls. Not the only but a newly missense variant in the present study, p. V463E (Exon 14+74 $T{\rightarrow}A$), was identified in exon 14 in 6 patients and 1 normal control. In exon 16, nt. 1678-80 del GTT with loss of heterozygosity (LOH) was identified in 27 CRC cases and 26 controls. There was no Y165C in exon 7 or G382D in exon 14, the hot-spot variants which have been reported most frequently in Caucasian studies. After univariate analysis and multivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 $A{\rightarrow}G$ (p=0.004) and p. V463E (p=0.036) in the MYH gene were selected as 3 independent risk factors for CRC. Conclusions: According to these results, the linked variant in Exon 1 region, Intron 10-2 $A{\rightarrow}G$ of base replacement and p. V463E of missense variant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility to sporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic difference in MYH gene.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.619-624
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• 2013

Background: Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditary forms, associated with the Lynch syndrome, familial adenomatous polyposis (FAP) and other rare syndromes. Sporadic CRC is believed to arise as a result of close interaction between environmental factors, including dietary and lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to the Lynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, in certain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable. Aim: To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whether it could play any role in modulating familial and sporadic CRC susceptibility risk. Methods: A case-control study comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynch syndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted from peripheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes were categorized into homozygous wild type, heterozygous and homozygous variants. The risk association between these polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis and deriving odds ratios (ORs). Results: When risk association was investigated for all CRC patients as a single group, the heterozygous (G/A) genotype showed a significantly higher risk for CRC susceptibility with an OR of 2.273, (95%CI: 1.133-4.558 and p-value=0.021). When analyzed specifically for the 2 types of CRC, the heterozygous (G/A) genotype showed significantly higher risk for sporadic CRC susceptibility with and OR of 3.714, (95%CI: 1.416-9.740 and p-value=0.008). Despite high OR value was observed for Lynch syndrome (OR: 1.600, 95%CI: 0.715-3.581), the risk was not statistically significant (P=0.253). Conclusion: Our results suggest an influence of MLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especially those with sporadic disease.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7683-7688
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• 2015

Background: The study evaluated the patient, lifestyle and tumor profile in patients undergoing upfront surgery for sporadic colorectal cancer (CRC) in Indian population. Materials and Methods: One hundred consecutive patients were included. Details related to their demographic profile, habits, signs and symptoms, tumor profile, further treatment and follow up were recorded. Results: The majority of the patients had colonic cancer (68%), advanced tumor stage 3 & 4 (46%), moderately differentiated tumors (70%) with absence of lymphatic invasion (60%) and metastasis (90%). Correlations between tumor location and abdominal pain (p-value 0.002), bleeding per rectum (p-value <0.001), difficulty in micturition (p-value 0.012) and constipation (p-value 0.007) were found to be statistically significant. Abdominal pain was more frequently reported in patients with metastasis (p-value 0.031). Loss of weight statistically correlated with absence of lymphatic invasion (p-value 0.047). Associations between tumor stage and alcohol intake (p-value 0.050) and non vegetarian diet (p-value 0.006); lymphatic invasion and intake of spicy food (p-value 0.040) and non vegetarian diet (p-value 0.001) and metastasis and alcohol intake (p-value 0.041) were also observed. Age and tumor grade were also correlated (p-value 0.020). Conclusions: Minimizing the adverse lifestyle factors can help in reducing the overall incidence of CRC in the Indian population.

• Biomedical Science Letters
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• v.9 no.3
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• pp.171-175
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• 2003

Microsatellite instability (MSI), which is caused by a deficient mismatch repair system, is seen in most of the hereditary non-polyposis colon cancers (HNPCC) and a portion of sporadic colorectal cancers. Forty unselected colorectal cancer patients were analyzed for MSI using silver stain plus kit. The overall incidence of MSI in studied cases was 17％ (7/40). The incidence is similar result with previous study. MSI in colorectal carcers was more prevalent in moderative differentiated adenocarcinoma than well differentiated adenocarcinoma