Aberrant Gene Promoter Methylation Associated with Sporadic Multiple Colorectal Cancer
Aberrant Gene Promoter Methylation Associated with Sporadic Multiple Colorectal Cancer
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DOI：
10.1371/journal.pone.0008777
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发表时间：
2010-01-19
期刊：
影响因子：
3.7
通讯作者：
Castells, Antoni
中科院分区：
文献类型：
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作者：
Gonzalo, Victoria;Jose Lozano, Juan;Castells, Antoni
背景：结直肠癌（CRC）的多样性主要与息肉病和非息肉病遗传综合征有关。在散发性CRC中，异常基因启动子甲基化已被证明在癌发生中起关键作用，尽管对其参与多重性知之甚少。为了评估甲基化对散发性CRC肿瘤多样性的影响，在多发性和孤立性肿瘤患者中评估了关键肿瘤抑制基因的超甲基化，作为潜在表观遗传缺陷的概念验证。方法学/主要发现：我们共检查了41例患者的47例同时/异时原发性CRC，41例性别，年龄（间隔5年）和肿瘤位置配对的孤立性肿瘤患者。排除标准为息肉综合征、Lynch综合征和炎症性肠病。采用甲基化特异性定量PCR检测肿瘤组织和相应的正常大肠粘膜组织中MGMT、CDKN 2A、SFRP 1、TMEFF 2、HS 3ST 2（3 OST 2）、RASSF 1A和GATA 4基因启动子区的DNA甲基化。总体而言，就所有评估的基因而言，具有多个病变的患者在肿瘤样品中表现出比具有孤立肿瘤的患者更高的甲基化程度。在调整年龄和性别后，二项逻辑回归分析确定了MGMT 2甲基化（OR，1.48; 95% CI，1.10至1.97; p = 0.008）和RASSF 1A（OR，2.04; 95% CI，1.01 ~ 4.13; p = 0.047）作为与肿瘤多样性独立相关的变量，与这两个基因中任何一个的甲基化相关的风险为4.57（95% CI，1.53至13.61; p = 0.006）。此外，在6名同时患有两种肿瘤的患者中，我们发现MGMT 2甲基化水平与肿瘤发生的相关性。（r = 0.64，p = 0.17）、SFRP 1（r = 0.83，0.06）、HPP 1（r = 0.64，p = 0.17）、3OST 2（r = 0.83，p = 0.06）和GATA 4（r = 0.6，p = 0.24）。在正常出现的结直肠粘膜中的多个和孤立的CRC患者的甲基化没有表现出相关的差异，在任何评估gene.Conclusions：这些结果提供了一个概念的证明，基因启动子甲基化与肿瘤的多样性。这种潜在的表观遗传缺陷可能对散发性CRC患者的预防具有重要意义。
Background: Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect.Methodology/Principal Findings: We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene.Conclusions: These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.