DNA demethylation in normal colon tissue predicts predisposition to multiple cancers.
DNA demethylation in normal colon tissue predicts predisposition to multiple cancers.
复制标题
DOI：
10.1038/onc.2011.652
复制
发表时间：
2012-11-29
期刊：
影响因子：
8
通讯作者：
Perucho, M.
中科院分区：
文献类型：
--
作者：
Kamiyama, H.;Suzuki, K.;Maeda, T.;Koizumi, K.;Miyaki, Y.;Okada, S.;Kawamura, Y. J.;Samuelsson, J. K.;Alonso, S.;Konishi, F.;Perucho, M.
一些结肠癌（CC）患者在诊断时出现同步性癌症，另一些患者出现异时性肿瘤，但非遗传性CC的风险因素尚不清楚。我们以前表明，全球DNA去甲基化随着年龄的增长而增加，并与CC中的基因组损伤相关，我们现在表明，优先与野生型p53的CC相关。本研究旨在阐明单个和多个CC患者的DNA低甲基化程度，其与衰老的关系，以及其作为预测工具的潜力。我们通过实时甲基化特异性PCR比较了来自单个和多个右侧CC患者的匹配癌组织和非癌性结肠粘膜（NCM）中长散布核苷酸元件-1（LINE-1）序列的相对去甲基化水平（RDL）。虽然在单个CC患者和健康志愿者的NCM中没有发现RDL差异（P =0.5），但在同步癌症患者的NCM中有更多的去甲基化（更高的RDL）（P =1.1 × 10−5），多个CC也比单个CC更多地去甲基化（P =0.0014）。高NCM去甲基化可预测异时性肿瘤（P =0.003）。在多变量logistic回归分析中，RDL是异时性（P =0.02）和多发性（P =4.9 × 10−5）肿瘤的唯一独立预测因子。多发性（同时性和异时性）肿瘤患者的NCM中LINE-1去甲基化水平较高（P =9.6 × 10−7），在无微卫星不稳定性（P =3.8 × 10−6）但无微卫星不稳定性（P =0.16）的肿瘤患者中也非常显著。NCM去甲基化在单个肿瘤患者中随年龄增加，但在多个肿瘤患者中减少。此外，年轻患者（P =3.6 × 10−4）的单肿瘤与多肿瘤患者之间的去甲基化差异高于老年患者（P =0.0016）。这些结果预测NCM中的LINE-1低甲基化可用作多种CC风险的表观遗传预测生物标志物。NCM中去甲基化与年轻患者多发性CC风险的更强相关性也表明了体细胞去甲基化的明显现场癌变效应的遗传易感性。
Some colon cancer (CC) patients present synchronous cancers at diagnosis and others develop metachronous neoplasms, but the risk factors are unclear for non-hereditary CC. We showed previously that global DNA demethylation increased with aging and correlated with genomic damage in CC, and we show now that preferentially associates to CCs with wild-type p53. This study aimed to elucidate the extent of DNA hypomethylation in patients with single and multiple CC, its relationship with aging, and its potential as predictive tool. We compared by real-time methylation-specific PCR the relative demethylation level (RDL) of long interspersed nucleotide element-1 (LINE-1) sequences in matched cancer tissues and non-cancerous colonic mucosa (NCM) from patients with single and multiple right-sided CCs. Although no RDL difference was found in NCM from single CC patients and healthy volunteers (P =0.5), there was more demethylation (higher RDL) in NCM from synchronous cancer patients (P =1.1 × 10−5) multiple CCs also were more demethylated than single CCs (P =0.0014). High NCM demethylation was predictive for metachronous neoplasms (P =0.003). In multivariate logistic regression analyses RDL was the only independent predictor for metachronous (P =0.02) and multiple (P =4.9 × 10−5) tumors. The higher LINE-1 demethylation in NCM from patients with multiple (synchronous and metachronous) tumors (P =9.6 × 10−7) was also very significant in patients with tumors without (P =3.8 × 10−6), but not with (P =0.16) microsatellite instability. NCM demethylation increased with aging in patients with single tumors, but decreased in those with multiple tumors. Moreover, the demethylation difference between patients with single vs multiple tumors appeared higher in younger (P =3.6 × 10−4) than in older (P =0.0016) patients. These results predict that LINE-1 hypomethylation in NCM can be used as an epigenetic predictive biomarker for multiple CC risk. The stronger association of demethylation in NCM with multiple CC risk from younger patients also suggests an inherited predisposition for the apparent field cancerization effect of somatic demethylation.
登录
查看更多内容
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
--
作者：
Qu, GZ;Grundy, PE;Ehrlich, M
通讯作者：
Ehrlich, M
影响因子：
3.7
作者：
Estecio, Marcos R. H.;Gharibyan, Vazganush;Shen, Lanlan;Ibrahim, Ashraf E. K.;Doshi, Ketan;He, Rong;Jelinek, Jaroslav;Yang, Allen S.;Yan, Pearlly S.;Huang, Tim H-M.;Tajara, Eloiza H.;Issa, Jean-Pierre J.
通讯作者：
Issa, Jean-Pierre J.
影响因子：
3.7
作者：
Gonzalo, Victoria;Jose Lozano, Juan;Castells, Antoni
通讯作者：
Castells, Antoni
DOI：
10.1093/jnci/djn359
发表时间：
2008-12-03
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Ogino, Shuji;Nosho, Katsuhiko;Fuchs, Charles S.
通讯作者：
Fuchs, Charles S.