Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study.
Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study.
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DOI：
10.1186/1476-4598-7-68
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发表时间：
2008-08-21
期刊：
影响因子：
37.3
通讯作者：
Ashktorab H
中科院分区：
文献类型：
--
作者：
Brim H;Mokarram P;Naghibalhossaini F;Saberi-Firoozi M;Al-Mandhari M;Al-Mawaly K;Al-Mjeni R;Al-Sayegh A;Raeburn S;Lee E;Giardiello F;Smoot DT;Vilkin A;Boland CR;Goel A;Hafezi M;Nouraie M;Ashktorab H
我们已经确定了散发性结肠癌中肿瘤发生的替代途径，涉及由于错配修复甲基化引起的微卫星不稳定性，这可能是由BRAF基因（V600 E）突变驱动的。结直肠癌（CRC）是世界上最常见的癌症，非洲裔美国人的发病率高于美国其他人群。我们分析了阿曼（非洲裔，N = 61），伊朗（高加索裔，N = 53）和非洲裔美国人（N = 95）患者的散发性CRC的微卫星不稳定性，错配修复基因（hMLH 1，hMSH 2）的表达状态和BRAF（V600 E）突变的存在。在阿曼组中，所有BRAF突变的肿瘤都位于结肠左侧，而对于非洲裔美国人，88%的BRAF突变肿瘤位于结肠右侧。在非裔美国人中，31%的肿瘤在两个或更多个标记物（MSI-H）上显示微卫星不稳定性，而伊朗和阿曼组的肿瘤中这一比例分别为26%和13%。在非裔美国人和伊朗受试者中，大多数MSI-H肿瘤位于近端结肠（右侧），而在阿曼受试者中，大多数位于远端结肠（左侧）。在非裔美国人和伊朗人的MSI-H肿瘤中发现了77%的hMLH 1基因表达缺陷，在阿曼人的肿瘤中发现了38%。在所有受试者中均观察到BRAF突变：非洲裔美国人中10%的肿瘤（8/82），伊朗人中2%的肿瘤（1/53）和阿曼人中19%的肿瘤（11/59）。我们的研究结果表明，在阿曼和伊朗患者中，CRC发生在较年轻的年龄，并且这些组的MSI-H发生率低于非洲裔美国患者。我们的多变量模型提示hMLH 1表达和BRAF突变在这些人群中的MSI-H CRC中具有重要和显著的作用。非裔美国人中MSI-H肿瘤的高发生率可能对治疗具有重要意义，因为MSI-H病变患者对化疗药物（如5-氟尿嘧啶）表现出不同的反应。
We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil.
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影响因子：
3.9
作者：
Fazeli, Mohhamad S.;Adel, Maryam Ghavami;Lebaschi, Amir H.
通讯作者：
Lebaschi, Amir H.
影响因子：
24.5
作者：
Jass, JR;Do, KA;Leggett, B
通讯作者：
Leggett, B
影响因子：
9.7
作者：
Ansari, Reza;Mahdavinia, Mahboobeh;Malekzadeh, Reza
通讯作者：
Malekzadeh, Reza
DOI：
10.1159/000083341
发表时间：
2005-01-01
期刊：
COMMUNITY GENETICS
影响因子：
--
作者：
Hassan, MO;Albarwani, S;Bayoumi, RA
通讯作者：
Bayoumi, RA
影响因子：
6.4
作者：
Chang, SC;Lin, JK;Chi, CW
通讯作者：
Chi, CW