Genetic instability on chromosome 17 in the epithelium of non‐polypoid colorectal carcinomas compared to polypoid lesions
Genetic instability on chromosome 17 in the epithelium of non‐polypoid colorectal carcinomas compared to polypoid lesions
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DOI：
10.1111/j.1349-7006.2006.00334.x
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发表时间：
2006-12
期刊：
影响因子：
5.7
通讯作者：
T. Ogawa;Tsutomu Yoshida;T. Tsuruta;K. Saigenji;I. Okayasu
中科院分区：
文献类型：
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作者：
T. Ogawa;Tsutomu Yoshida;T. Tsuruta;K. Saigenji;I. Okayasu
早期结直肠癌（粘膜下浸润性腺癌）可分为息肉样生长癌（PG‐Ca）和非息肉样生长癌（NPG‐Ca）两种类型，后者转化为晚期癌的速度更快。先前，我们指出基质遗传不稳定性可能有助于散发性和溃疡性结肠炎相关结直肠癌的肿瘤发生。在本研究中，我们分析了PG‐Ca和NPG‐Ca中上皮和周围基质成分的遗传不稳定性。在99例结直肠粘膜下浸润性腺癌中，使用美国国家癌症研究所标准微卫星标记、17号染色体（chr17）标记和肿瘤抑制基因相关标记，结合激光捕获显微解剖和GeneScan方法，分析了上皮和间质遗传不稳定性。对hMLH1、hMSH2、MGMT、p53进行免疫组化分析。此外，我们还研究了hMLH1和MGMT启动子的甲基化。与PG‐Ca（10.4%）相比，NPG‐Ca中带有Chr.17标记的上皮微卫星不稳定性（MSI）的频率显著更高（33.3%），尤其是D17S579和D17S796。杂合性缺失方面，只有D17S786差异显著。所有标记间质MSI在NPG‐Ca和PG‐Ca中的频率分别为31.7%和25.9%，但D17S579和TP53在NPG‐Ca中的MSI高于PG‐Ca。免疫组织化学结果显示，与没有遗传不稳定性的患者相比，总体上chr17标记改变的杂合性阳性患者（尤其是D17S796标记）中p53蛋白在PG‐Ca中的表达明显更高。这些结果表明，在NPG‐Ca中，Chr.17标记物的上皮和间质MSI对癌变的贡献更大，而间质遗传不稳定可能是两种类型结直肠癌发生的必要条件。（癌症科学2006；97:1335-1342）
Early colorectal carcinomas (submucosal invasive adenocarcinomas) can be classified into polypoid growth carcinoma (PG‐Ca) and non‐polypoid growth carcinoma (NPG‐Ca) types, the latter transforming more rapidly to advanced carcinoma. Previously, we indicated that stromal genetic instability might contribute to tumorigenesis of both sporadic and ulcerative colitis‐associated colorectal adenocarcinomas. In the present study, we analyzed genetic instability of both epithelial and surrounding stromal components in PG‐Ca and NPG‐Ca. In 99 colorectal submucosal invasive adenocarcinomas, epithelial and stromal genetic instability was analyzed with National Cancer Institute standard microsatellite markers, chromosome 17 (Chr.17) markers and tumor suppressor gene‐related markers, using a combination of the laser‐captured microdissection and GeneScan approaches. Immunohistochemical analysis was carried out for hMLH1, hMSH2, MGMT and p53. In addition, we investigated methylation of the hMLH1 and MGMT promoters. The frequencies of epithelial microsatellite instability (MSI) with Chr.17 markers were significantly higher in NPG‐Ca (33.3%) compared to PG‐Ca (10.4%), particularly with D17S579 and D17S796. For loss of heterozygosity, only D17S786 showed a significant difference. The frequencies of stromal MSI with all markers were 31.7% and 25.9% in NPG‐Ca and PG‐Ca, respectively, but D17S579 and TP53 showed higher MSI in NPG‐Ca than PG‐Ca. Immunohistochemically, p53 protein expression in PG‐Ca was significantly higher in loss of heterozygosity‐positive cases with altered Chr.17 markers overall, especially the D17S796 marker, compared to cases without genetic instability. These results suggest that epithelial and stromal MSI of Chr.17 markers contributes more to carcinogenesis in NPG‐Ca, whereas stromal genetic instability might be necessary for the development of both types of colorectal carcinoma. (Cancer Sci 2006; 97: 1335–1342)