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Investigation of colorectal carcinogenesis for genetic diagnosis

结直肠癌发生机制的基因诊断研究

基本信息

批准号：
17591402
负责人：
KAMBARA Takeshi
金额：
$ 2.24万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

There is increasing evidence that not only genetic but also epigenetic alterations are involved in many types of carcinogenesis. We have been studied molecular mechanisms of colorectal carcinogenesis using microsatellite, mutation and methylation analysis. Recently, we have found that the BRAF mutation was frequently seen in a subset of hyperplastic polyp (HP), termed as sessile serrated adenoma (SSA) and in sporadic colorectal cancer (CRC) showing high level microsatellite instability (MSI-H), both of which were associated with CpG island methylator phenotype (CIMP). We have first reported that sporadic MSI-H CRC may originate in SSA and not adenoma, and BRAF mutation and DNA methylation are early event in this "serrated neoplastic pathway" distinct from the accepted "adenoma-carcinoma-sequence" [Gut 53(8): 1137-1144, 2004]. Moreover, we have reported that promoter hypermethylation and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H CRC [Familiar C … More ancer 3(2): 101-107, 2004].The colorectal polyps are classified into HP, mixed polyp, serrated adenoma (SA), villous adenoma and conventional adenoma using WHO criteria. Classifying HPs into microvesicular and goblet cell-type HP, and SAs into traditional SA and variant HP described as "SSA", we screened these precursor lesions and CRCs for activating mutation of oncogene KRAS and BRAF, inactivating mutation of tumor suppressor gene APC, and methylation status of CpG island. In contrast to well accepted multi-step model of mutation accumulation, we found that few CRC contained mutations in KRAS, BRAF and APC and almost CRC had mutation in only one of these genes. The most common combination of mutations was APC and KRAS (11.2%), whereas mutations in both APC and BRAF/KRAS were extremely rare (1.1%/0%). Similar mutational pattern was also observed in colon polyps. On the other hand, we confirmed that aberrant DNA methylation is only a disease of older individuals with MSI-H cancer but in associated with all subsets of colorectal cancers. These results suggest that multiple genetic pathways to CRC exist and that mutation in APC and CIMP negative was an early event in adenoma-carcinoma sequence, while mutation in KRAS/BRAF and CIMP-positive predispose to serrated neoplastic pathway. Less

越来越多的证据表明，不仅遗传而且表观遗传改变参与了许多类型的癌症发生。我们已经利用微卫星、突变和甲基化分析研究了结直肠癌发生的分子机制。最近，我们发现BRAF基因突变常见于称为固定性锯齿状腺瘤(SSA)的增生性息肉(HP)和表现为高水平微卫星不稳定性(MSI-H)的散发性结直肠癌(CRC)，这两种突变均与CpG岛甲基化表型(CIMP)相关。我们首次报道了散发性MSI-H CRC可能起源于SSA而不是腺瘤，并且BRAF突变和DNA甲基化是这一“锯齿状肿瘤通路”的早期事件，不同于公认的“腺瘤-癌-序列”[Gut 53(8)：1137-1144,2004]。此外，我们已经报道，启动子超甲基化和BRAF突变区分遗传性非息肉病性结肠癌和散发性微卫星H结肠癌[熟悉的C…根据WHO标准将大肠息肉分为幽门螺杆菌、混合性息肉、锯齿状腺瘤、绒毛状腺瘤和普通型腺瘤。将HPS分为微泡型和杯状细胞型，SAS分为传统SA和变异型Hp(称为“SSA”)，对这些先兆病变和癌前病变的癌基因KRAS和BRAF的激活突变、抑癌基因APC的失活突变和CpG岛的甲基化状态进行筛选。与公认的多步突变累积模型相比，我们发现很少有CRC在KRAS、BRAF和APC中存在突变，几乎所有的CRC只在其中一个基因上有突变。APC和KRAS是最常见的突变组合(11.2%)，而APC和BRAF/KRAS突变极少(1.1%/0%)。在结肠息肉中也观察到了类似的突变模式。另一方面，我们证实，DNA甲基化异常只是一种老年MSI-H癌症患者的疾病，但与结直肠癌的所有亚型都相关。这些结果表明，大肠癌的发生存在多种遗传途径，APC和CIMP阴性突变是腺瘤-癌序列中的早期事件，而KRAS/BRAF突变和CIMP阳性突变易发生锯齿状肿瘤通路。较少

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer.

DOI：
10.1016/s1542-3565(04)00673-1
发表时间：
2005-03
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
0
作者：
Joanne P Young;M. Barker;L. Simms;M. Walsh;K. Biden;D. Buchanan;R. Buttenshaw;V. Whitehall;
通讯作者：
Joanne P Young;M. Barker;L. Simms;M. Walsh;K. Biden;D. Buchanan;R. Buttenshaw;V. Whitehall;

Oesophageal squamous cell cancer may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa

食管鳞状细胞癌可能在正常和发育不良粘膜中积累 DNA 甲基化的背景下发生

DOI：
发表时间：
2007
期刊：
GUT 56
影响因子：
0
作者：
Ishii T;Murakami J;Notohara K;Cullings HM;Sasamoto H;Kambara T;Shirakawa Y;Naomoto Y;Ouchida M;Shimizu K;Tanaka N;Jass JR;Matsubara N
通讯作者：
Matsubara N

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis.

溃疡性结肠炎上皮内观察到的异质微卫星不稳定性。

DOI：
发表时间：
2006
期刊：
Int. J. Cancer 119 (11)
影响因子：
0
作者：
Ozaki;K.;Nagasaka;T.;Notohara;K.;Kambara;T.;Takeda;M.;Sasamoto;H.;Jass;J.R.;Tanaka;N.;Matsubara;N.
通讯作者：
N.

DNA methylation patterns in adenomas from FAP, multiple adenoma and sporadic colorectal carcinoma patients.

FAP、多发性腺瘤和散发性结直肠癌患者腺瘤中的 DNA 甲基化模式。