Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.
BMC Cancer. 2010 Oct 27;10:587. doi: 10.1186/1471-2407-10-587.
Only a few studies have addressed the molecular pathways specifically involved in carcinogenesis of the distal colon and rectum. We aimed to identify potential differences among genetic alterations in distal colon and rectal carcinomas as compared to cancers arising elsewhere in the large bowel.
Constitutional and tumor DNA from a test series of 37 patients with rectal and 25 patients with sigmoid carcinomas, previously analyzed for microsatellite instability (MSI), was studied for BAX, IGF2R, TGFBR2, MSH3, and MSH6 microsatellite sequence alterations, BRAF and KRAS mutations, and MLH1 promoter methylation. The findings were then compared with those of an independent validation series consisting of 36 MSI-H carcinomas with origin from each of the large bowel regions. Immunohistochemical and germline mutation analyses of the mismatch repair system were performed when appropriate.
In the test series, IGFR2 and BAX mutations were present in one and two out of the six distal MSI-H carcinomas, respectively, and no mutations were detected in TGFBR2, MSH3, and MSH6. We confirmed these findings in the validation series, with TGFBR2 and MSH3 microsatellite mutations occurring less frequently in MSI-H rectal and sigmoid carcinomas than in MSI-H colon carcinomas elsewhere (P = 0.00005 and P = 0.0000005, respectively, when considering all MSI-carcinomas of both series). No MLH1 promoter methylation was observed in the MSI-H rectal and sigmoid carcinomas of both series, as compared to 53% found in MSI-H carcinomas from other locations (P = 0.004). KRAS and BRAF mutational frequencies were 19% and 43% in proximal carcinomas and 25% and 17% in rectal/sigmoid carcinomas, respectively.
The mechanism and the pattern of genetic changes driving MSI-H carcinogenesis in distal colon and rectum appears to differ from that occurring elsewhere in the colon and further investigation is warranted both in patients with sporadic or hereditary disease.
仅有少数研究涉及专门涉及远端结肠和直肠癌变的分子途径。我们旨在确定远端结肠癌和直肠癌与大肠其他部位癌症相比，遗传改变之间的潜在差异。
对先前分析微卫星不稳定性（MSI）的 37 例直肠癌和 25 例乙状结肠癌患者的测试系列的体质和肿瘤 DNA，进行 BAX、IGF2R、TGFBR2、MSH3 和 MSH6 微卫星序列改变、BRAF 和 KRAS 突变以及 MLH1 启动子甲基化研究。然后将这些发现与由来自大肠各个区域的 36 例 MSI-H 癌组成的独立验证系列进行比较。当适当时，进行错配修复系统的免疫组织化学和种系突变分析。
在测试系列中，IGF2R 和 BAX 突变分别存在于 6 例 MSI-H 远端结肠癌中的 1 例和 2 例中，而 TGFBR2、MSH3 和 MSH6 未检测到突变。我们在验证系列中证实了这些发现，与 MSI-H 结肠癌相比，MSI-H 直肠和乙状结肠癌中 TGFBR2 和 MSH3 微卫星突变发生的频率较低（当考虑两个系列中的所有 MSI-癌时，P = 0.00005 和 P = 0.0000005）。与其他部位的 MSI-H 癌相比，两个系列的 MSI-H 直肠和乙状结肠癌均未观察到 MLH1 启动子甲基化（P = 0.004）。近端癌中 KRAS 和 BRAF 突变频率分别为 19%和 43%，直肠/乙状结肠癌中分别为 25%和 17%。
驱动远端结肠和直肠 MSI-H 癌变的机制和遗传变化模式似乎与大肠其他部位的癌变不同，因此无论是在散发性还是遗传性疾病患者中，都需要进一步研究。
