Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.
Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.
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DOI：
10.18632/oncotarget.2852
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Perucho M
中科院分区：
文献类型：
--
作者：
Alonso S;Dai Y;Yamashita K;Horiuchi S;Dai T;Matsunaga A;Sánchez-Muñoz R;Bilbao-Sieyro C;Díaz-Chico JC;Chernov AV;Strongin AY;Perucho M
O6-甲基鸟嘌呤-DNA 甲基转移酶基因 (MGMT) 的体细胞高甲基化先前被认为与结直肠癌 (CRC) 中 KRAS 和 TP53 的 G > A 过渡突变相关。我们测试了 261 个 CRC 中 MGMT 甲基化与 KRAS 和 TP53 中 G > A 突变的关联。通过外显子组测序进一步分析了 16 例有或没有 MGMT 高甲基化的病例。未发现 MGMT 甲基化与 KRAS、TP53 或整个外显子组中的 G > A 突变存在显着关联（所有比较中 p > 0.5）。通过与癌症基因组图谱 (TCGA) 联盟数据集中的 302 个 CRC 进行计算机比较来验证结果。转录沉默与高甲基化相关，分为单等位基因和双等位基因。我们还在 CRC 患者的正常结肠粘膜中发现 MGMT 和基质金属蛋白酶基因 ADAMTS14 的异常高甲基化显着聚集 (p = 0.001)。这表明存在癌化的表观遗传场缺陷，破坏了包括 MGMT 或 ADAMTS14 在内的多个位点的甲基化模式，这可能会产生 CRC 的预测生物标志物。正常粘膜中这些位点的甲基化在老年患者 (p = 0.001) 中更为常见，特别是在非裔美国人 (p = 1 × 10−5) 中，因此在北美的体细胞表观遗传改变和 CRC 种族差异之间提供了可能的机制联系。
Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene (MGMT) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found (p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering (p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci, including MGMT or ADAMTS14, that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder (p = 0.001) patients, and particularly in African Americans (p = 1 × 10−5), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
11.5
作者：
Amatu, Alessio;Sartore-Bianchi, Andrea;Siena, Salvatore
通讯作者：
Siena, Salvatore
影响因子：
56.9
作者：
FINNEY, RE;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
--
作者：
Kast RE;Boockvar JA;Brüning A;Cappello F;Chang WW;Cvek B;Dou QP;Duenas-Gonzalez A;Efferth T;Focosi D;Ghaffari SH;Karpel-Massler G;Ketola K;Khoshnevisan A;Keizman D;Magné N;Marosi C;McDonald K;Muñoz M;Paranjpe A;Pourgholami MH;Sardi I;Sella A;Srivenugopal KS;Tuccori M;Wang W;Wirtz CR;Halatsch ME
通讯作者：
Halatsch ME
影响因子：
45.3
作者：
Black, D;Soslow, RA;Boyd, J
通讯作者：
Boyd, J