Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer
Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer
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DOI：
10.1053/gast.1996.v111.pm8690195
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发表时间：
1996-08-01
期刊：
影响因子：
29.4
通讯作者：
Miyaki, M
中科院分区：
文献类型：
--
作者：
Konishi, M;KikuchiYanoshita, R;Miyaki, M
背景与目的：微卫星不稳定性(复制错误[RER])是遗传性非息肉病性结肠癌(HNPCC)肿瘤的特征，但HNPCC的致癌机制尚不清楚。为了明确HNPCC肿瘤的性质，比较了HNPCC和非HNPCC肿瘤的RER和基因改变。方法：采用聚合酶链式反应、单链构象多态分析、测序和Southern杂交等方法，对21例HNPCC、389例家族性腺瘤性息肉病和206例散发性肿瘤的ER和基因改变进行分析。结果：在HNPCC中，95%的各期肿瘤均呈RER阳性(4.3个基因位点改变)。在家族性腺瘤性息肉病和散发性肿瘤中，RER阳性率在腺瘤和粘膜内癌中为3%(1.7/5)，在浸润性癌中为13%~24%，在肝转移癌中为35%。50%的RER阳性HNPCC肿瘤同时存在hMSH2或hMLH1基因的种系和体细胞突变，而6%的RER阳性非HNPCC肿瘤存在体细胞突变。HNPCC中APC、P53、K-ras-2突变和抑癌基因杂合性丢失的发生率显著低于非HNPCC(P=0.03~0.0006)，而转化生长因子βII受体突变的发生率显著高于非HNPCC(P=0.000001)。结论：在HNPCC中，RER阳性发生在癌变的早期阶段，而在非HNPCC中，则发生在癌变的晚期。大多数HNPCC肿瘤可能是通过与腺瘤-癌序列不同的基因变化而发展起来的，尽管有一定比例的肿瘤是通过APC突变来发展的。
Background & Aims: Microsatellite instability (replication error [RER]) is a characteristic of tumors in hereditary nonpolyposis colon cancer (HNPCC), but the mechanism of HNPCC carcinogenesis is not yet understood. To clarify the nature of HNPCC tumors, RER and genetic changes were compared between HNPCC and non-HNPCC tumors. Methods: RER and genetic changes were analyzed in 21 HNPCC, 389 familial adenomatous polyposis, and 206 sporadic tumors using polymerase chain reaction, single-strand conformation polymorphism, sequencing, and Southern hybridization. Results: In HNPCC, 95% tumors at all stages showed RER positivity (altered loci, 4.3 of 5). In familial adenomatous polyposis and sporadic tumors, RER positivity (1.7 of 5) was 3% in adenoma and intramucosal carcinoma, 13%-24% in invasive carcinoma, and 35% in carcinoma metastasized to liver. Fifty percent of RER-positive HNPCC tumors had both germline and somatic mutations of hMSH2 or hMLH1 gene, whereas 6% of RER-positive non-HNPCC had somatic mutation. APC, p53, and K-ras-2 mutations and loss of heterozygosity of tumor-suppressor genes were significantly less frequent (P = 0.03 to 0.0006) but transforming growth factor beta type II receptor mutation was significantly more frequent (P = 0.000001) in HNPCC than in non-HNPCC. Conclusions: RER positivity occurs from an early stage of carcinogenesis in HNPCC but in later stages in non-HNPCC. Most HNPCC tumors may develop through different genetic changes from those in the adenoma-carcinoma sequence, although a certain percentage develops through APC mutation.