2007 Fiscal Year Final Research Report Summary
Genetic and epigenetic analyses of folate and nudeotide metabolizing enzymes in gastrointestinal cancer
| Project/Area Number |
18591458
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Kanazawa University |
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Principal Investigator |
KAWAKAMI Kazuyuki Kanazawa University, Cancer Research Institute, Associate Professor (00293358)
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| Project Period (FY) |
2006 – 2007
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| Keywords | colorecral cancer / Thymidvlate synthase / gene polymorphism / loss of heterozygosity / methylator phenotype / gamma-glutamyl hydrolase / DNA methylation |
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| Research Abstract |
In this project, we analyzed mRNA expression and gene polymorphisms of Nate and nucleotide metabolizing enzymes in primary colorectal cancer (CRC). The results of the genetic analyses were then compared to dinical information and epigenetic alterations. There were two major findings in the study.
Firstly, we found that loss of heterozygosity (LOH) on Thymidylate synthase (TS) locus is significant prognostic factor in CRC and influences TS genotype on tumor. The hundred and twenty six CRC cases were analyzed for VNTR and SNP on TS gene, and for the LOH status on TS locus.2G allele was rare and no 2R allele with G C SNP in the first tandem repeat was found in our population. Therefore, SNP in 2R allele was not considered and the genotyping was conducted with 3 allele types, 2R, 3G, and 3C, in the following analyses. There was no statistically significant association between the TS genotype in normal and clinicopathological features. TS LOH was observed in 90(58.0%) tumor samples. TS LOH p
… More
ositive case was significantly correlated with poor prognosis independent to clinical stage In TS LOH(+) cases, the genotype can be stratified into three, 2R/loss, 3G/loss, and 3C/loss. The prognosis of patients with 3C/loss genotype was poorer without postoperative5-FU-basedadjuvant chemotherapy but was equivalent to those with other genotypes when receiving the adjuvant chemotherapy.
Secondly, we found that CRC with CpG island methylatior phenotype (CIMP+) is associated with low expression of gamma-glutamyl hydrolase (GGII), suggesting involvement of the folate pathway in the development and/or progression of this phenotype. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RTPCR CIMP+ was determined by real time methylation specific PCR and compared to mRNA expression. Candidate genes showing association with CUP+ were further investigated in a replication cohort of150 CRC samples from Japan. In the exploratory study; GGH mRNA egression was strongly associated with CRAP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC.
The results in this project provided knowledge for future development of tailored chemotherapy using genetic and epigenetic molecular markers. Less
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