Epigenetic alteration: new insights moving from tissue to plasma - the example of PCDH10 promoter methylation in colorectal cancer.
Epigenetic alteration: new insights moving from tissue to plasma - the example of PCDH10 promoter methylation in colorectal cancer.
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DOI：
10.1038/bjc.2013.351
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发表时间：
2013-08-06
影响因子：
8.8
通讯作者：
Lippi G
中科院分区：
文献类型：
--
作者：
Danese E;Minicozzi AM;Benati M;Montagnana M;Paviati E;Salvagno GL;Gusella M;Pasini F;Guidi GC;Lippi G
血液中肿瘤释放的DNA是一种很有前途的癌症检测生物标志物。虽然表观遗传学改变，如异常的启动子甲基化代表了一个吸引人的前景，但从肿瘤组织提取的DNA和无细胞DNA(CfDNA)中发现的改变频率之间存在的不一致已经挑战了它们的实际临床应用。为了解释这种一致性偏差，我们调查了组织中原钙粘蛋白10(PCDH10)启动子的甲基化是否与从结直肠癌患者血浆中分离的匹配cfDNA的甲基化模式有关，以及一致性的强度是否取决于cfDNA水平、完整性指数以及不同的临床病理特征。应用定量甲基化特异性聚合酶链式反应分析了67例肿瘤组织、配对的正常粘膜和匹配的血浆样本中PCDH10启动子中选定的CpG位点。用实时定量聚合酶链式反应检测cfDNA完整性指数和cfDNA浓度。67例手术切除的大肠肿瘤中63例(94.0%)和67例血浆标本中42例(62.7%)检测到PCDH10启动子甲基化。肿瘤组织和血浆中甲基化的中位数分别为43.5%(6.3-97.8%)和5.9%(0-80.9%)。在早期结直肠癌患者中，cfDNA中PCDH10甲基化与肿瘤组织有显著相关性(P<；0.0001)。血浆和组织甲基化比率在早期癌症中随cfDNA完整性指数的增加而增加(P=0.0299)，在晚期癌症中随cfDNA绝对浓度的增加而增加(P=0.0234)。我们的发现为调节组织和血浆甲基化特征之间的一致性的生物学方面提供了新的见解。
Tumour-released DNA in blood represents a promising biomarker for cancer detection. Although epigenetic alterations such as aberrant promoter methylation represent an appealing perspective, the discordance existing between frequencies of alterations found in DNA extracted from tumour tissue and cell-free DNA (cfDNA) has challenged their practical clinical application. With the aim to explain this bias of agreement, we investigated whether protocadherin 10 (PCDH10) promoter methylation in tissue was associated with methylation pattern in matched cfDNA isolated from plasma of patients with colorectal cancer (CRC), and whether the strength of concordance may depend on levels of cfDNA, integrity index, as well as on different clinical–pathological features. A quantitative methylation-specific PCR was used to analyse a selected CpG site in the PCDH10 promoter of 67 tumour tissues, paired normal mucosae, and matched plasma samples. The cfDNA integrity index and cfDNA concentration were assessed using a real-time PCR assay. The PCDH10 promoter methylation was detected in 63 out of 67 (94.0%) surgically resected colorectal tumours and in 42 out of 67 (62.7%) plasma samples. The median methylation rate in tumour tissues and plasma samples was 43.5% (6.3–97.8%) and 5.9% (0–80.9%), respectively. There was a significant correlation between PCDH10 methylation in cfDNA and tumour tissue in patients with early CRC (P<0.0001). The ratio between plasma and tissue methylation rate increases with increasing cfDNA integrity index in early-stage cancers (P=0.0299) and with absolute cfDNA concentration in advanced cancers (P=0.0234). Our findings provide new insight into biological aspects modulating the concordance between tissues and plasma methylation profiles.
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