Sporadic colon cancer: Mismatch repair immunohistochemistry and microsatellite instability in omani subjects
Sporadic colon cancer: Mismatch repair immunohistochemistry and microsatellite instability in omani subjects
复制标题
DOI：
10.1007/s10620-007-0189-3
复制
发表时间：
2008-10-01
影响因子：
3.1
通讯作者：
Raeburn, Sandy
中科院分区：
文献类型：
--
作者：
Ashktorab, Hassan;Brim, Hassan;Raeburn, Sandy
结直肠癌（Colorectal carcinoma，CRC）是世界上最常见的胃肠道恶性肿瘤，在中东地区发病率特别高，包括非洲地区。DNA错配修复（MMR）系统的缺陷参与了散发性和遗传性人类癌症的致癌作用。我们评估了结肠癌，试图确定与DNA MMR缺陷和微卫星不稳定性（MSI）的肿瘤。此外，我们测试了细胞周期调节因子p16影响细胞增殖的能力，并且可以通过启动子区域的超甲基化而被废除。方法：我们回顾了2000年至2004年期间在阿曼苏丹卡布斯大学医院和皇家医院的主要结肠镜检查单位就诊的756例患者的病历。使用免疫组织化学测定结肠癌组织中hMLH 1和hMSH 2的表达，并使用一组五对微卫星引物（NR 21、NR 22、NR 24、BAT 25和BAT 26）进行MSI-H分析，使用额外的二核苷酸标记物（D17 S250、D5 S346和D2 S123）进行MSI-L分析。MMR基因和MSI的表达状态与癌症分期、部位和组织学相关。共49个肿瘤进行了组织病理学，MSI和hMLH 1/hMSH 2蛋白表达分析。通过甲基化特异性聚合酶链反应（PCR）确定p16启动子的甲基化状态。结果本组患者平均年龄52.2岁，男性占53%。大多数肿瘤位于左侧。现有信息表明，在这些中心接受结肠镜检查的病例中，结肠癌的发病率为4.7%（49/1036），结肠腺瘤的发病率为12.1%（126/1290）。MSI-H的发生率为12.2%（n = 6），与文献报道的相同。免疫组化结果显示，49例肿瘤中有8例（16.3%）为MMR缺陷型。错配修复基因hMLH 1和hMSH 2的缺陷分别在4例（66.7%）和2例（33.3%）CRCs MSI-H病例中发现。肿瘤中hMLH 1表达缺陷通常与中度分化相关。p16启动子在4%的肿瘤中被甲基化。结论这是世界上第一个在该地区进行的CRC遗传学研究，证实了阿曼人群中MSI、p16甲基化、hMLH 1和MSH 2表达的发生率。此外，还注意到年轻年龄组的CRC发生率相对较高，这是一个重要的观察结果。MMR缺陷型肿瘤的左侧优势主要与hMLH 1相关，并可能与hMSH 2表达缺失相关，这一观察结果与其他人群的研究不同。总之，尽管该地区CRC的总体发病率未知，但该地区CRC中MSI的频率似乎与美国白人相同。
Background Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy in the world, and there are suggestions of a particularly high incidence in the Middle East, including those of African origin. Defects in DNA mismatch repair (MMR) systems are involved in the carcinogenesis of both sporadic and inherited human cancers. We assessed colonic cancers in an attempt to identify tumors with DNA MMR deficiency and microsatellite instability (MSI). Additionally, we tested the ability of cell cycle regulator p16 that effects cell proliferation and can be abrogated by hypermethylation of the promoter region. Methods We reviewed the charts of 756 patients who were referred to the Oman major colonoscopy unit of the Sultan Qaboos University Hospital and Royal Hospital from the years 2000 to 2004. Colon cancer tissue was assayed using immunohistochemistry for expression of hMLH1 and hMSH2, and a panel of five pairs of microsatellite primers (NR21, NR22, NR24, BAT25, and BAT26) for MSI-H analysis and additional dinucleotide markers (D17S250, D5S346, and D2S123) used for MSI-L. The expression status of MMR genes and MSI was correlated with cancer stage, location, and histology. A total of 49 tumors were analyzed for histopathology, MSI, and hMLH1/hMSH2 protein expression analysis. The methylation status of the p16 promoter was determined by methylation-specific polymerase chain reaction (PCR). Results The mean age for the carcinomas was 52.2 years and 53% of the patients were male. The majority of the tumors were left-sided. The information currently available indicates that there is an incidence of 4.7% colon cancer (49/1036) and 12.1% (126/1290) colon adenoma among the cases who underwent colonoscopy at these centers. The rate of MSI-H was 12.2% (n = 6), which appears to be the same as previously reported in literature. Eight of 49 tumors (16.3%) were MMR defective by IHC. Defects in the mismatch repair genes hMLH1 and hMSH2 were found in four (66.7%) and two (33.3%) of CRCs MSI-H cases, respectively. Defects in hMLH1 expression in tumors were commonly associated with moderate differentiation. The p16 promoter was methylated in 4% of tumors. Conclusion This is the first genetic study of CRC in this region of the world to demonstrate the incidence of MSI, p16 methylation, and hMLH1 and MSH2 expression in the Omani population. In addition, a relatively high frequency of CRC in younger age groups was noted, which is an important observation. The left-sided preponderance of MMR defective tumors was mostly associated with hMLH1, and with possible loss of hMSH2 expression, an observation that differs from studies on other populations. In conclusion, although the overall rate of CRC is unknown in this region, the frequency of MSI in CRC in this region appears to be the same as in Caucasians in the USA.