Brücher Björn L D M, Geddert Helene, Langner Cord, Höfler Heinz, Fink Ulrich, Siewert Jörg R, Sarbia Mario
Department of Surgery, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany.
Int J Cancer. 2006 Sep 15;119(6):1298-302. doi: 10.1002/ijc.21990.
Small bowel adenocarcinoma (SB-AC) is a very rare tumor entity. Epigenetic alterations, including hypermethylation of DNA mismatch repair genes and tumor suppressor genes, seem to be important for carcinogenesis in tumors of the gastrointestinal tract, but have not yet been investigated in SB-AC. In the current study, the prevalence of hypermethylation in a panel of genes involved in gastrointestinal carcinogenesis (hMLH1, HPP1, p14(ARF), p16(INK4A), APC) was determined in a series of SB-AC. Paraffin-embedded tumor samples from 56 patients with SB-AC who underwent surgical resection between January 1985 and December 2003 were investigated for hypermethylation by means of methylation-specific real-time PCR, and compared with our findings in a previously investigated series of 50 gastric adenocarcinomas. In comparison with adenocarcinomas of the stomach, SB-AC revealed a significantly higher rate of hypermethylation of HPP1 (86% versus 54%, p = 0.0003), p16(INK4A) (32% versus 10%, p = 0.0006), and a significantly lower rate of hypermethylation of APC (48% versus 84%, p = 0.0001). Hypermethylation of hMLH1 and p14(ARF) was present in 23% and 9% of SB-AC, respectively. Locally advanced tumor categories (pT3/4) showed a higher rate of hypermethylation of HPP1 (90%) than did early tumor categories (pT1/2 categories, 40%; p = 0.0036). This was also reflected by the correlation between the HPP1 hypermethylation and high UICC stage (p = 0.02). No correlation was found between hypermethylation and other clinicopathologic parameters such as age, tumor grade and nodal status. Our findings suggest that hypermethylation of hMLH1, HPP1, p16(INK4A) and APC is frequent in primary adenocarcinomas of the small bowel. The differences in the hypermethylation spectrum of small bowel and stomach cancer indicate significant epigenetic differences between these tumors.
小肠腺癌（SB - AC）是一种非常罕见的肿瘤类型。表观遗传改变，包括DNA错配修复基因和肿瘤抑制基因的高甲基化，似乎对胃肠道肿瘤的致癌作用很重要，但尚未在小肠腺癌中进行研究。在当前研究中，在一系列小肠腺癌中确定了参与胃肠道致癌作用的一组基因（hMLH1、HPP1、p14(ARF)、p16(INK4A)、APC）的高甲基化发生率。对1985年1月至2003年12月期间接受手术切除的56例小肠腺癌患者的石蜡包埋肿瘤样本，通过甲基化特异性实时PCR检测高甲基化情况，并与我们之前研究的50例胃腺癌系列的结果进行比较。与胃腺癌相比，小肠腺癌显示出HPP1高甲基化率显著更高（86%对54%，p = 0.0003），p16(INK4A)高甲基化率显著更高（32%对10%，p = 0.0006），而APC高甲基化率显著更低（对84%，p = 0.0001）。hMLH1和p14(ARF)的高甲基化分别出现在23%和9%的小肠腺癌中。局部晚期肿瘤类别（pT3/4）显示出HPP1高甲基化率（90%）高于早期肿瘤类别（pT1/2类别，40%；p = 0.0036）。这也反映在HPP1高甲基化与高UICC分期之间的相关性上（p = 0.02）。未发现高甲基化与年龄、肿瘤分级和淋巴结状态等其他临床病理参数之间存在相关性。我们的研究结果表明，hMLH1、HPP1、p16(INK4A)和APC的高甲基化在原发性小肠腺癌中很常见。小肠癌和胃癌高甲基化谱的差异表明这些肿瘤之间存在显著的表观遗传差异。
