Lee Jae-Hyuk, Abraham Susan C, Kim Hyun-Soo, Nam Jong-Hee, Choi Chan, Lee Min-Cheol, Park Chang-Soo, Juhng Sang-Woo, Rashid Asif, Hamilton Stanley R, Wu Tsung-Teh
Department of Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Am J Pathol. 2002 Aug;161(2):611-8. doi: 10.1016/S0002-9440(10)64216-2.
Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.
胃癌在全球范围内都很常见，但胃癌发生的遗传机制尚未完全明确。胃息肉样腺瘤和平坦发育异常被视为癌前病变。然而，尚未对这些病变进行详细的分子研究以确定它们作为癌前病变的作用。我们研究了35例无腺癌的腺瘤和47例平坦发育异常、35例与腺癌相关的腺瘤/发育异常以及39例腺癌（20例弥漫型和19例肠型）中APC、β-连环蛋白和K-ras基因的突变以及微卫星不稳定性（MSI）状态。在76%（78例中的59例）无相关腺癌的腺瘤或平坦发育异常中发现了体细胞APC基因突变，但在仅3%（30例中的1例）与腺癌相关的腺瘤/发育异常中以及仅4%（69例中的3例）的腺癌中发现了该突变（P<0.000001）。在无APC突变且无β-连环蛋白突变的腺癌或腺瘤/发育异常中未发现β-连环蛋白突变。在82例无癌的胃腺瘤/发育异常中有5%（4例）检测到K-ras突变，在39例无相关腺瘤/发育异常的腺癌中有3%（1例）检测到K-ras突变，而在32例有相关腺瘤/发育异常的腺癌中未检测到。与癌相关的胃腺瘤/发育异常中高水平MSI（MSI-H）比无癌的腺瘤/发育异常更常见（17%，35例中的6例比3%，75例中的2例；P=0.01）。MSI-H在肠型腺癌中也比弥漫型更常见（20%，54例中的11例比0%，20例中的0例；P=0.03）。在9例低水平MSI的胃腺瘤/发育异常中有6例（67%）存在APC基因突变，但在8例具有MSI-H表型的腺瘤/发育异常中均未发现（P=0.009）。我们的结果表明，APC基因的体细胞突变在胃腺瘤和发育异常的发病机制中起重要作用，但在向腺癌的肿瘤进展中作用有限。无APC突变但有或无MSI的胃腺瘤或发育异常可能具有不同的生物学行为，并且是肠型胃腺癌的前体。
