Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans.
Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans.
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非洲裔美国人的高微卫星不稳定性大结直肠癌的独特BRAF（V600E）和KRAS突变。
DOI：
10.1158/1078-0432.ccr-08-1029
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发表时间：
2009-02-15
期刊：
影响因子：
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通讯作者：
Ashktorab H
中科院分区：
文献类型：
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作者：
Kumar K;Brim H;Giardiello F;Smoot DT;Nouraie M;Lee EL;Ashktorab H
结直肠癌是通过导致不受控制的细胞增殖的遗传、表观遗传和环境事件而发生的。非裔美国人 (AA) 的结直肠癌发病率和死亡率高于一般人群。在这里，我们对来自 AA 的散发性结直肠癌肿瘤进行了分子分析，以研究观察到的差异的可能解释。通过免疫组织化学分析了总共 222 个 AA 结直肠癌肿瘤中两个 DNA 错配修复基因 MLH1 和 MSH2 蛋白表达的微卫星不稳定性 (MSI)；通过甲基化特异性 PCR 对 MLH1、p16、APC 和 APC2 启动子进行甲基化沉默；通过测序发现两个癌基因 KRAS 和 BRAF 的点突变。在我们的样本中，19.8% 的 AA 结直肠癌肿瘤具有高 MSI (MSI-H)，并且与除肿瘤分化外的任何临床病理特征无关。免疫组织化学发现较高水平的无活性 DNA 错配修复蛋白 MLH1 (41%) 和 MSH2 (33%)。甲基化特异性 PCR 分析显示 MLH1 (66%)、APC (53%) 和 APC2 (90%) 甲基化水平较高，但 p16 (26%) 甲基化水平较低。 BRAF 突变仅出现在 MSI-H 肿瘤中，而大多数 (64%) KRAS 突变出现在非 MSI-H 组中。与 APC、APC2 和 KRAS 改变不同，MLH1、MSH2 和 BRAF 改变与 MSI-H 表型显着相关。这项研究支持 DNA 错配修复基因抑制在 MSI-H 中的突出作用以及 BRAF 和 KRAS 突变对 MSI 状态的独特作用
Colorectal cancer develops through genetic, epigenetic, and environmental events that result in uncontrolled cell proliferation. Colorectal cancer incidence and mortality is higher in African Americans (AA) than in the general population. Here, we carried out a molecular analysis of sporadic colorectal cancer tumors from AAs to investigate possible explanations for the observed disparities. A total of 222 AA colorectal cancer tumors were analyzed for micro-satellite instability (MSI) for protein expression of two DNA mismatch repair genes, MLH1 and MSH2, by immunohistochemistry; for the methylation silencing of MLH1, p16, APC, and APC2 promoters by methylation-specific PCR; and for point mutations in two oncogenes, KRAS and BRAF, by sequencing. In our sample, 19.8% of the AAs colorectal cancer tumors were MSI high (MSI-H) and did not associate with any of the clinicopathologic features, except tumor differentiation. Higher levels of inactive DNA mismatch repair proteins MLH1 (41%) and MSH2 (33%) were found by immunohistochemistry. Methylation-specific PCR analysis revealed a high level of methylation for MLH1 (66%), APC (53%), and APC2 (90%), but not for p16 (26%). BRAF mutations were only within the MSI-H tumors, whereas most (64%) of KRAS mutations were found within the non – MSI-H group. MLH1, MSH2, and BRAF alterations are significantly associated with MSI-H phenotype, unlike APC, APC2 and KRAS alterations. The prominent role of DNA mismatch repair gene suppression in MSI-H and a distinctive role of BRAF and KRAS mutations with respect to MSI status are supported by this study