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Identification of tumor suppressor genes in human pancreatic cancer

人胰腺癌抑癌基因的鉴定

基本信息

批准号：
07457046
负责人：
HORII Akira
金额：
$ 3.26万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457046/
关键词：
tumor suppressor gene oncogene human pancreatic cancer chromosome 12q chromosome 20q TGF beta receptor type II IGFII receptor DNA mismatch repair error TGFBβレセプターII型染色体欠失

项目摘要

We first searched for imbalances of copy number in human pancreatic cancer cells using more than 100 primary tumor and corresponding normal tissues as well as 12 cell lines by (i) LOH study with microsatellite markers of all chromosome arms except for short arms of acrocentric chromosomes and sex chromosomes and (ii) comparative genomic hybridization (CGH). Frequent gains of chromosome arms 8q and 20q, and losses of 1p, 6q, 9p, 12q, 17p, and 18q were observed.We further focused on allelic loss of chromosome arm 12q and constructed a detailed deletion map. Finally we identified a 1-cM region of common allelic loss. We further constructed a contig in this region with YAC and BAC clones, and found that a YAC colne of 790 kb in size harbored the whole region of common allelic loss. We are now constructing a cosmid contig in this region.Region of the gain of chromosome 8q overlapped with the region of the c-myc oncogene. Region of the gain of chromosome 20q was evaluated for its precise region and copy number by fluorescence in situ hybridization (FISH). Copy number was increased by two-fold, and the region was overlapped with that of breast cancer.Involvement of DNA mismatch repair error was also analyzed in this study. Frequent microsatellite instability (MI) was observed (13% of the tumors). None of the mutations in hMSH2 and hMLH1 were observed in tumors with MI+.Moreover, somatic mutations of neither the transforming growht factor (TGF) beta receptor type II (RII) gene nor the insulin-like growht factor II receptor (IGFIIR) gene were found which were frequently observed in colorectal, gastric, and endometrial cancers with MI+. These results suggested that mutations of these genes do not play an important role, if any, in pancreatic carcinogenesis.

我们首先利用100多个原发肿瘤和相应的正常组织以及12个细胞系，通过(I)除端着丝粒染色体和性染色体短臂外的所有染色体臂的微卫星标记的LOH研究和(Ii)比较基因组杂交(CGH)来寻找人胰腺癌细胞拷贝数的不平衡。观察到染色体臂8q和20q的频繁获得，1p、6q、9p、12q、17p和18q的丢失，并进一步关注了染色体臂12q的等位基因缺失，构建了详细的缺失图谱。最后，我们确定了一个1 cM的常见等位基因缺失区域。我们进一步用YAC和BAC克隆构建了该区域的重叠群，发现790kb的YAC克隆包含了整个共同等位基因缺失的区域。我们现在正在构建这个区域的粘粒重叠群，染色体8q的获得区与c-myc癌基因的区域重叠。用荧光原位杂交(FISH)检测20Q染色体增殖区的精确区域和拷贝数。该基因的拷贝数增加了一倍，并与乳腺癌的拷贝数重叠，并分析了DNA错配修复错误的演变。经常观察到微卫星不稳定性(MI)(13%的肿瘤)。在MI+的肿瘤中未发现hMSH2和hMLH1的突变。此外，也没有发现转化生长因子β受体II(RII)基因和胰岛素样Groht因子II受体(IGFIIR)基因的体细胞突变，这在MI+的结直肠癌、胃癌和子宫内膜癌中常见。这些结果表明，如果有的话，这些基因的突变在胰腺癌的发生中并不起重要作用。