Clinicopathological features and microsatellite instability (MSI) in colorectal cancers from African Americans
Clinicopathological features and microsatellite instability (MSI) in colorectal cancers from African Americans
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DOI：
10.1002/ijc.21062
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发表时间：
2005-10-10
影响因子：
6.4
通讯作者：
Giardiello, FM
中科院分区：
文献类型：
--
作者：
Ashktorab, H;Smoot, DT;Giardiello, FM
非裔美国人（AAs）患结直肠癌（CRC）的风险比白人高1.5倍。通过CpG岛超甲基化的基因沉默与微卫星不稳定性（MSI）的发生或进展相关，这主要是由于超甲基化的1个靶点是DNA错配修复基因hMLH 1;有轶事证据表明AA中MSI的发生率增加。P16和hMLH 1可以通过其各自启动子区域的超甲基化而失活，从而消除调节细胞增殖和修复过程的能力。我们研究了这种甲基化，以及hMHS 2在AA患者结直肠癌中的表达，以确定MSI是否与表观遗传沉默相关。在来自AA患者的匹配的正常和结肠癌组织（n=51）上进行实验。应用5个微卫星标记（D2 S123、D5 S346、D17 S250、BAT 25和BAT 26）评价MSI状态。P16和hMLH 1启动子甲基化状态在DNA的亚硫酸氢盐修饰和使用甲基化特异性PCR后测定，而免疫组织化学（IHC）用于检测hMLH 1和hMSH 2的表达。共有22例（43%）癌症显示微卫星不稳定性高（MSI-H），而27例微卫星稳定（MSS）和2例微卫星不稳定性低（MSH-L）。大多数MSI-H肿瘤位于近端，分化良好，高粘液性。MSI-H组的大多数患者为女性（68%）。47例肿瘤中有19例（40%）p16启动子甲基化。这些CRC中共有7例表现为MSI-H（33%）。hMLH 1启动子在34例肿瘤中的29例（85%）中甲基化，其中13例CRC表现为MSI-H（87%）。在MSI-H肿瘤中分别观察到66%和38%的hMLH 1和hMSH 2染色。总体而言，MSI-H结直肠肿瘤的患病率高2-3倍，而AA患者中错配修复（MMR）基因（hMLH 1和hMSH 2）表达百分比的缺陷与美国白人人群相似。具有p16和hMLH 1甲基化的AA MSS肿瘤的相似数量可能表明可能反映环境或遗传影响的基因的半甲基化，这可能在AA人群中更常见。(C)2005 Wiley-Liss，Inc.
African Americans (AAs) have a 1.5 times higher risk of colorectal carcinoma (CRC) than Caucasians. Gene silencing through CpG island hypermethylation has been associated with the genesis or progression of microsatellite instability (MSI) largely due to 1 target for hypermethylation being the DNA mismatch repair gene hMLH1; there is anecdotal evidence of an increased incidence of MSI among AAs. P16 and hMLH1 can be inactivated by hypermethylation of their respective promoter regions, abrogating the ability to regulate cell proliferation and repair processes. We studied such methylation, as well as hMHS2 expression in colorectal cancers from AA patients to determine if MSI is associated with epigenetic silencing. Experiments were conducted on matched normal and colon cancer tissues from AA patients (n=51). A total of 5 microsatellite markers (D2S123, D5S346, D17S250, BAT25 and BAT26) were used to evaluate MSI status. P16 and hMLH1 promoter methylation status was determined following bisulfite modification of DNA and using methylation specific PCR, while immunohistochemistry (IHC) was used to examine expression of hMLH1 and hMSH2. A total of 22 (43%) cancers demonstrated microsatellite instability-high (MSI-H), while 27 were microsatellite stable (MSS) and 2 were microsatellite instability-low (MSH-L). Most of the MSI-H tumors were proximal, well differentiated and highly mucinous. Most patients in the MSI-H group were females (68%). The p16 promoter was methylated in 19 of 47 (40%) tumors. A total of 7 of these CRCs demonstrated MSI-H (33%). The hMLH1 promoter was methylated in 29 of 34 (85%) tumors, of which 13 CRCs demonstrated MSI-H (87%). hMLH1 and hMSH2 staining was observed in 66% and 38% of MSI-H tumors, respectively. Overall, the prevalence of MSI-H colorectal tumor was 2-3-fold higher, while the defect in the percentage expression of mismatch repair (MMR) genes (hMLH1 and hMSH2) was similar in AA patients compared to the U.S. Caucasian population. Similar numbers of AA MSS tumors with p16 and hMLH1 methylation likely indicate hemimethylation of genes that might reflect environmental or genetic influences that might be more common in the AA population. (C) 2005 Wiley-Liss, Inc.