核酸・葉酸代謝関連酵素の包括的遺伝子解析による消化器癌の個別化医療開発

• Material Type: 文書・図像類
• Title: 核酸・葉酸代謝関連酵素の包括的遺伝子解析による消化器癌の個別化医療開発
• Author/Editor: 川上, 和之; Kawakami, Kazuyuki
• Author Heading: 川上, 和之; Kawakami, Kazuyuki
• Publication, Distribution, etc.: 金沢大学がん研究所
• Publication Date: 2010-02-03
• Publication Date (W3CDTF): 2010-02-03
• Alternative Title: Genetic and epigenetic analyses of folate and nudeotide metabolizing enzymes in gastrointestinal cancer
• Periodical title: 平成19(2007)年度 科学研究費補助金 基盤研究(C) 研究成果報告書概要 = 2007 Fiscal Year Final Research Report Summary
• No. or year of volume/issue: 2006-2007
• Volume: 2006-2007
• Pages: 3p.-
• Text Language Code: jpn
• Subject Heading: 大腸癌; Thymidylate synthase; gene polymorphism; loss of heterozygosity; methylator phenotype; gamma-glutamyl hydrolase; DNAメチル化; colorecral cancer; Thymidvlate synthase; DNA methylation
• Target Audience: 一般
• Note (General): 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 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.; 本研究では、大腸がん組織における核酸・葉酸代謝関連酵素の遺伝子変化・多型性を包括的に解析し、これを癌の臨床病理学的特徴やDNAメチル化などのエピジェネティックな変化と対比することにより、遺伝子解析に基づく大腸がんの理解を進めた。さらに、各解析項目と抗癌剤の感受性との関連を探索し、オーダーメイド抗癌剤治療の科学的基盤を構築した。チミジル酸合成酵素(以下TS)の遺伝子型とTS遺伝子座におけるアレル欠失(loss of heterozygosity、以下LOH)を大腸癌症例を対象に解析し、その予後因子・抗癌剤感受性因子としての臨床的意義を検討した。TSLOHを認める症例は有意に予後不良であり、18番染色体長腕のLOHと相関する変化であった。TS LOHを認めた症例では、遺伝子型3C/lossの予後が不良であったが、術後補助化学療法を受けた症例ではその予後は他の遺伝子型(2R/loss、3G/loss)と同等であった。DNAメチル化の異常と核酸・葉酸代謝の変化との関連を理解するため、大腸がん114検体を対象として、核酸・葉酸代謝にかかわる17遺伝子のmRNA発現を定量した。その結果、gamma-glutamyl hydrolase(GGH)のmRNA発現はDNAメチル化を高頻度に伴う表現型CpG island methylator phenotype(CIMP)癌で有意に低値であった。GGHは葉酸代謝の中心的酵素であることから、大腸がんにおけるDNAメチル化の獲得・維持には葉酸代謝の破綻が少なからず関連していると考えられた。以上の結果から、核酸・葉酸代謝酵素遺伝子の遺伝子型やDNAメチル化の状態を指標として主に代謝拮抗剤の効果予測・治療の個別化へと臨床展開可能であることが示唆され、オーダーメイド医療開発への基盤的研究成果を得た。; 研究課題/領域番号:18591458, 研究期間(年度):2006-2007; 出典：研究課題「核酸・葉酸代謝関連酵素の包括的遺伝子解析による消化器癌の個別化医療開発」課題番号18591458（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18591458/185914582007kenkyu_seika_hokoku_gaiyo/）を加工して作成
• DOI: 10.24517/00057340
• Access Restrictions: 限定公開
• Related Material: https://kaken.nii.ac.jp/search/?qm=00293358; https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591458/; https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18591458/185914582007kenkyu_seika_hokoku_gaiyo/
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA