Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma.
Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma.
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DOI：
10.1186/1476-4598-6-70
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发表时间：
2007-10-29
期刊：
影响因子：
37.3
通讯作者：
Laird-Offringa IA
中科院分区：
文献类型：
--
作者：
Tsou JA;Galler JS;Siegmund KD;Laird PW;Turla S;Cozen W;Hagen JA;Koss MN;Laird-Offringa IA
肺癌是美国男性和女性的头号癌症杀手。四分之三的肺癌患者被诊断为地区性或远处播散性疾病；他们的5年生存率只有15%。启动子CpG岛上的DNA超甲基化显示出作为癌症特异性标记的巨大前景，这将补充螺旋CT等可视化肺癌筛查工具，提高早期发现。在肺癌患者中，从肿瘤材料到血液和痰的各种样本中都可以检测到这种甲基化。到目前为止，DNA甲基化在任何单个基因座上的外显率都太低，不能提供很高的临床敏感性。我们采用实时荧光定量聚合酶链式反应方法，对51例人肺腺癌、38例癌旁肺组织和11例非肺癌患者的肺组织中的28个基因座的DNA甲基化进行了定量检测。我们确定了13个在肿瘤和非肿瘤肺之间存在显著差异的基因位点甲基化水平；其中8个在腺癌中表现出高度显著的甲基化：CDH13、CDKN2AEX2、CDX2、HOXA1、OPCML、RASSF1、SFPR1和Twist1(p-Value<；0.0001)。利用当前的组织收集和5倍交叉验证，四个最显著的基因座(CDKN2AEX2、CDX2、HOXA1和OPCML)分别区分肺腺癌和非癌肺，敏感性为67-86%，特异性为74-82%。这些基因座的DNA甲基化在性别、种族、年龄或肿瘤分期方面没有显著差异，表明它们作为潜在的肺腺癌标记物具有广泛的适用性。我们应用随机森林根据我们的基因座的一个子集来确定一个好的分类器，并确定联合使用相同的四个顶级标记可以以94%的灵敏度和90%的特异度识别肺癌组织和非肺癌组织。8个在肺腺癌中表现出高度显著甲基化的CpG岛基因座的鉴定为患者血浆和痰等远程介质的评估提供了强有力的候选。CDKN2AEX2、CDX2、HOXA1和OPCML这四个排名最高的基因座，即使在IA期肿瘤样本中也显示出显著的DNA甲基化，值得进一步研究，作为迄今为止被发现的最有希望的肺腺癌标记物。
Lung cancer is the number one cancer killer of both men and women in the United States. Three quarters of lung cancer patients are diagnosed with regionally or distantly disseminated disease; their 5-year survival is only 15%. DNA hypermethylation at promoter CpG islands shows great promise as a cancer-specific marker that would complement visual lung cancer screening tools such as spiral CT, improving early detection. In lung cancer patients, such hypermethylation is detectable in a variety of samples ranging from tumor material to blood and sputum. To date the penetrance of DNA methylation at any single locus has been too low to provide great clinical sensitivity. We used the real-time PCR-based method MethyLight to examine DNA methylation quantitatively at twenty-eight loci in 51 primary human lung adenocarcinomas, 38 adjacent non-tumor lung samples, and 11 lung samples from non-lung cancer patients. We identified thirteen loci showing significant differential DNA methylation levels between tumor and non-tumor lung; eight of these show highly significant hypermethylation in adenocarcinoma: CDH13, CDKN2A EX2, CDX2, HOXA1, OPCML, RASSF1, SFPR1, and TWIST1 (p-value << 0.0001). Using the current tissue collection and 5-fold cross validation, the four most significant loci (CDKN2A EX2, CDX2, HOXA1 and OPCML) individually distinguish lung adenocarcinoma from non-cancer lung with a sensitivity of 67–86% and specificity of 74–82%. DNA methylation of these loci did not differ significantly based on gender, race, age or tumor stage, indicating their wide applicability as potential lung adenocarcinoma markers. We applied random forests to determine a good classifier based on a subset of our loci and determined that combined use of the same four top markers allows identification of lung cancer tissue from non-lung cancer tissue with 94% sensitivity and 90% specificity. The identification of eight CpG island loci showing highly significant hypermethylation in lung adenocarcinoma provides strong candidates for evaluation in patient remote media such as plasma and sputum. The four most highly ranked loci, CDKN2A EX2, CDX2, HOXA1 and OPCML, which show significant DNA methylation even in stage IA tumor samples, merit further investigation as some of the most promising lung adenocarcinoma markers identified to date.
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影响因子：
14.9
作者：
LAIRD, PW;ZIJDERVELD, A;BERNS, A
通讯作者：
BERNS, A
DOI：
10.1073/pnas.87.9.3294
发表时间：
1990-05-01
影响因子：
11.1
作者：
MANECKJEE, R;MINNA, JD
通讯作者：
MINNA, JD
影响因子：
6.4
作者：
Guo, MingZhou;House, Michael G.;Herman, James G.
通讯作者：
Herman, James G.
影响因子：
4.7
作者：
Liu, Y;An, Q;Gao, YN
通讯作者：
Gao, YN
影响因子：
8
作者：
Shiraishi, M;Sekiguchi, A;Miyamoto, Y
通讯作者：
Miyamoto, Y