Young Joanne, Barker Melissa A, Simms Lisa A, Walsh Michael D, Biden Kelli G, Buchanan Daniel, Buttenshaw Ron, Whitehall Vicki L J, Arnold Sven, Jackson Leigh, Kambara Takeshi, Spring Kevin J, Jenkins Mark A, Walker Graeme J, Hopper John L, Leggett Barbara A, Jass Jeremy R
Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research, Herston, Australia.
Clin Gastroenterol Hepatol. 2005 Mar;3(3):254-63. doi: 10.1016/s1542-3565(04)00673-1.
Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members.
A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island.
All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) ( P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs ( P < .05).
These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development.
最近，在结直肠癌中发现了一种与锯齿状前驱病变、微卫星不稳定性（MSI-V）水平各异相关的肿瘤发生替代途径，部分由BRAF原癌基因（V599E）的激活突变驱动。遗传性非息肉病性结肠癌（HNPCC）中很少观察到体细胞BRAF突变。在此，我们讨论它们在其他家族性结直肠癌（CRC）发生中的作用。我们研究了非FAP、非HNPCC的CRC家系，其特征是家族成员个体肿瘤的MSI水平各不相同。
对来自11个家系43名个体的总共55个采集样本（25个息肉和30个癌症）中的一部分肿瘤进行病理检查，使用等位基因特异性聚合酶链反应检测V599E，并检测MINT31 CpG岛的甲基化情况。
所有MSI-V家系均符合当前修订的贝塞斯达指南，11个家系中有6个（55%）符合阿姆斯特丹I标准。在19个息肉中的12个（63%）和20个癌症中的14个（70%）观察到V599E（4个高MSI中的4个，4个低MSI中的2个，12个稳定MSI中的8个），显著高于HNPCC（15个中的0个或0%）和未选择的CRC（197个中的30个或15.2%）（P <.05）。接受分析的10个癌症中有8个（80%）显示MINT31甲基化。CRC发病年龄较早，与未选择的CRC相比，更可能呈现锯齿状结构（P <.05）。
这些数据提供了证据，表明此处描述的家系代表一种与HNPCC不同的家族性CRC综合征。高水平的BRAF突变和MINT31甲基化提示其起源于CRC发展的锯齿状途径。
