Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer.
Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer.
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DOI：
10.1016/s1542-3565(04)00673-1
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发表时间：
2005-03
期刊：
影响因子：
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通讯作者：
Joanne P Young;M. Barker;L. Simms;M. Walsh;K. Biden;D. Buchanan;R. Buttenshaw;V. Whitehall;
中科院分区：
文献类型：
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作者：
Joanne P Young;M. Barker;L. Simms;M. Walsh;K. Biden;D. Buchanan;R. Buttenshaw;V. Whitehall;
背景与目的最近，在结直肠癌中发现了与锯齿状前体病变、不同程度的微卫星不稳定性(MSI-V)相关的另一种肿瘤发生途径，部分原因是BRAF原癌基因(V599E)的激活突变。遗传性非息肉病性结肠癌(HNPCC)的体细胞BRAF突变很少观察到。在这里，我们讨论它们在其他家族性结直肠癌(CRC)发展中的作用。我们研究了非FAP、非HNPCC CRC家系，其特征是肿瘤在个体成员之间的MSI水平不同。方法收集来自11个家系43人的55个肿瘤(25个息肉和30个癌症)，进行病理复习，使用等位基因特异性聚合酶链式反应检查V599E，以及MINT31 CpG岛的甲基化。结果所有MSI-V家系都符合当前修订的Bethesda指南，11个家系中有6个(55%)符合阿姆斯特丹I标准。V599E在19例息肉中阳性12例(63%)，在20例癌中阳性14例(70%)(4例高MSI中4例，4例低MSI中2例，12例稳定MSI中8例)，显著高于HNPCC(0/15或0%)和非选择性结直肠癌(30/197或15.2%)(P<；0.05)。在接受分析的10例癌症中，有8例(80%)显示出MINT31的高甲基化。结直肠癌的发病年龄较早，并且比未选择的结直肠癌更容易表现为锯齿状结构(P<；0.05)。结论这些数据提供了证据，表明这里描述的家族性结直肠癌是一种有别于HNPCC的家族性结直肠癌综合征。高水平的BRAF突变和MINT31高甲基化提示其起源于结直肠癌的锯齿状发展过程。
Background & AimsRecently, 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.MethodsA 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.ResultsAll 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).ConclusionThese 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.