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Miyakura Y.,Jichi Medical University | Sugano K.,Tochigi Cancer Center Research Institute | Nomizu T.,Hoshi General Hospital | Lefor A.,Jichi Medical University | Yasuda Y.,Jichi Medical University
Japanese Journal of Clinical Oncology

Lynch syndrome is caused by germline mutations of the DNA mismatch repair genes. Missense mutations are often difficult to evaluate as pathogenic. Previously, we reported a missense mutation in exon 12 at codon 600 of the MSH2 gene, causing a substitution of GTT (Val) for GCT (Ala) in a 35-year-old-man with rectal cancer, while the pathogenicity of this mutation is still unclear. In this report, we confirm the same mutation in his 66-year-old mother who had cecal cancer. PCR/direct sequencing analysis of peripheral blood lymphocytes revealed the same missense mutation in exon 12 at codon 600 of the MSH2 gene. The wave height of the capillary sequencer from the wild-type allele was decreased in tumor tissue, indicating loss of heterozygosity in the wild-type allele. Analysis of the tumor showed microsatellite instability high and loss of MSH2 protein expression. This sequence variant has not been reported in another family. This mutation is considered to play a significant and causative role in Lynch syndrome. © The Author 2011. Published by Oxford University Press. All rights reserved. Source

Hashimoto T.,National Cancer Center Hospital | Ogawa R.,National Cancer Center Research Institute | Matsubara A.,National Cancer Center Hospital | Taniguchi H.,National Cancer Center Hospital | And 6 more authors.

Aims: Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome caused by a germline APC mutation. A recent study showed the enrichment of pyloric gland adenomas (PGAs) of the stomach, in addition to fundic gland polyps (FGPs) and foveolar-type adenomas (FAs), in patients with FAP. In the present study, we analysed the genetic alterations in these FAP-associated gastric lesions. Methods and results: Mutational statuses of GNAS and KRAS, which are frequently mutated in sporadic PGAs, as well as those of APC, were examined in PGAs, FAs and FGPs in patients with FAP using Sanger sequencing. Our analysis identified GNAS mutations in five of six PGAs (83%), but in none of the three FAs or the 40 FGPs examined. KRAS mutations were identified in four PGAs (67%), one FA (33%) and one FGP (3%). Somatic truncating APC mutations were found in all PGAs (100%), two FAs (67%) and 14 FGPs (47%). We additionally analysed sporadic PGAs of the stomach and duodenum and identified truncating APC mutations in 11 of 25 lesions (44%). Conclusions: FAP-associated and sporadic PGAs not only show similar morphologies, but also share common genetic aberrations, including mutations of GNAS, KRAS and APC. © 2015 John Wiley & Sons Ltd. Source

Wolff E.M.,University of Southern California | Chihara Y.,University of Southern California | Pan F.,University of Southern California | Weisenberger D.J.,University of Southern California | And 6 more authors.
Cancer Research

Urothelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invasive tumors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is also characterized by a high rate of recurrence, and the presence of a field defect has been postulated. In this study, we compared the DNA methylation patterns between noninvasive and invasive UC and the DNA methylation patterns between normal-appearing urothelium from bladders with cancer and urothelium from cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 noninvasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urothelium from 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the noninvasive tumors and widespread hypermethylation in the invasive tumors, confirming that the two pathways differ epigenetically in addition to genetically. We also found that 12% of the loci were hypermethylated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field defect. X-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion but occurred independently across the urothelium of bladders with cancer. The hypomethylation present in noninvasive tumors may counterintuitively provide a biological explanation for the failure of these tumors to become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise. ©2010 AACR. Source

BACKGROUND: Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A; rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients.METHODS: Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis.RESULTS: Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n=54), 51% (n=108) and 23% (n=48), respectively, and they were significantly associated with the methylation status (p=0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p=0.0094), especially in females (p=0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p=0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation.CONCLUSIONS: These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter region. Source

Kotake K.,Tochigi Cancer Center | Mizuguchi T.,Tochigi Cancer Center | Moritani K.,Tochigi Cancer Center | Wada O.,Tochigi Cancer Center | And 3 more authors.
International Journal of Colorectal Disease

Purpose: The clinical significance of D3 lymph node dissection for patients with colon cancer remains controversial. This study aims to clarify the impact of D3 lymph node dissection on survival in patients with colon cancer. Methods: This is a retrospective cohort study from a prospectively registered multi-institutional database of colorectal cancer in Japan. Propensity score matching method was applied to balance potential confounders of the treatment. A cohort of 10,098 patients who underwent radical colectomy for pT3 and pT4 colon cancer between 1985 and 1994 were identified. A total of 3,425 propensity score matched pairs were extracted from the entire cohort. The primary outcome measure was overall survival (OS). Results: In the entire cohort, there was a statistically significant difference in overall survival (OS) between the patients who had D3 and D2 lymph node dissection (p=0.00003). The estimated hazard ratio (HR) for OS of patients who had D3 versus D2 lymph node dissection was 0.827 (95 % confidence interval, 0.757 to 0.904). In the matched cohort, there was also a significant difference in OS between the two groups (p=0.0001), and the estimated HR for OS was 0.814 (95 % confidence interval, 0.734 to 0.904). Conclusions: We found D3 lymph node dissection for pT3 and pT4 colon cancer to be associated with a significant survival advantage in a large-scale database, even after adjusting potential confounders of lymph node dissection. This finding may provide a rationale for D3 lymph node dissection in radical surgery for pT3 and pT4 colon cancer. © 2014 Springer-Verlag. Source

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