Miyaki M, Nishio J, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Nagato M, Chong J M, Koike M, Terada T, Kawahara Y, Fukutome A, Tomiyama J, Chuganji Y, Momoi M, Utsunomiya J
Department of Biochemistry, The Tokyo Metropolitan Institute of Medical Science, Japan.
Oncogene. 1997 Dec 4;15(23):2877-81. doi: 10.1038/sj.onc.1201668.
Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.
Turcot综合征的特征是患者在青少年时期出现恶性脑肿瘤和结肠癌。由于Turcot综合征的致癌机制尚不清楚，我们分析了一名无该疾病家族史的Turcot患者肿瘤中的基因变化。所有肿瘤，包括1例星形细胞瘤、3例结肠癌和2例结肠腺瘤，均表现出严重的复制错误（RER），并且所有结肠肿瘤在TGFbetaRII、E2F-4、hMSH3和/或hMSH6基因的重复区域均显示体细胞突变。在3例结肠癌中的3例检测到体细胞APC突变，在星形细胞瘤和3例结肠癌中的2例检测到体细胞p53突变，这两者均显示两个突变且无等位基因缺失。我们还发现，与通常正常组织中RER非常罕见的遗传性非息肉病性结直肠癌（HNPCC）患者相比，该患者的正常结肠黏膜、正常皮肤成纤维细胞和正常脑组织分别显示出较高频率的RER。这些结果表明，正常组织中极端的DNA不稳定性导致了Turcot综合征中多种癌症的早期发生。在该患者的一个等位基因中检测到hPMS2基因第705密码子的错义突变（GAG突变为AAG），该等位基因从其无肿瘤的母亲遗传而来。其他未知的种系突变可能导致正常组织中的基因不稳定。
