Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Konishi F, Utsunomiya J, Miyaki M
Department of Biochemistry, Tokyo Metropolitan Institute of Medical Science, Japan.
Gastroenterology. 1996 Aug;111(2):307-17. doi: 10.1053/gast.1996.v111.pm8690195.
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.
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.
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.
微卫星不稳定性（复制错误 [RER]）是遗传性非息肉病性结直肠癌（HNPCC）肿瘤的一个特征，但HNPCC致癌机制尚不清楚。为阐明HNPCC肿瘤的本质，比较了HNPCC与非HNPCC肿瘤之间的RER和基因变化。
采用聚合酶链反应、单链构象多态性、测序和Southern杂交技术，对21例HNPCC、389例家族性腺瘤性息肉病和206例散发性肿瘤的RER和基因变化进行分析。结果：在HNPCC中，各阶段95%的肿瘤显示RER阳性（改变的位点，5个中有4.3个）。在家族性腺瘤性息肉病和散发性肿瘤中，RER阳性（5个中有1.7个）在腺瘤和黏膜内癌中为3%，在浸润性癌中为13% - 24%，在肝转移癌中为35%。50%的RER阳性HNPCC肿瘤同时有hMSH2或hMLH1基因的种系和体细胞突变，而6%的RER阳性非HNPCC有体细胞突变。与非HNPCC相比，HNPCC中APC、p53和K-ras-2突变以及肿瘤抑制基因杂合性缺失的频率显著较低（P = 0.03至0.0006），但转化生长因子βⅡ型受体突变的频率显著较高（P = 0.000001）。
RER阳性在HNPCC致癌的早期阶段出现，而在非HNPCC中出现在后期阶段。大多数HNPCC肿瘤可能通过与腺瘤 - 癌序列不同的基因变化发展而来，尽管有一定比例是通过APC突变发展而来。
