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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma
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The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma

机译:间皮瘤中肿瘤MSLN甲基化与血清间皮素(SMRP)的关系

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摘要

Malignant pleural mesothelioma (MPM) remains a cancer of poor prognosis. It is hoped that implementation of effective screening biomarkers will lead to earlier diagnoses and improved outcomes. Serum-measured soluble mesothelin-related peptide (SMRP) has been demonstrated to have excellent specificity for MPM, but poor sensitivity precludes its use as a screening biomarker. Using a case series of MPM patients from the International Mesothelioma Program at the Brigham and Women's hospital, we sought to determine whether epigenetic change at the MSLN gene in patient tumors is responsible for the poor sensitivity of SMRP. We identified three potential target regions for CpG methylation silencing in the MSLN promoter, one of which was amenable to bisulfite pyrosequencing and located 214 bp upstream of the transcription start site. MSLN promoter methylation was significantly higher in normal pleura than tumor tissue (p 6.0 x 10 -9). Next, we compared cases according to serum SMRP status and observed that MSLN methylation was significantly higher among tumors from patients testing negative for SMRP (1.5 nM) versus those that were SMRP positive (p 0.03). These results demonstrate that MSLN is normally methylated in the pleura, and that methylation is lost in most tumors. However, in a subset of tumors methylation is retained, and this mechanism explains the poor sensitivity of the SMRP assay. These results may lead to additional biomarker targets that will resolve the poor sensitivity of the SMRP assay and allow implementation of screening among exposed populations.
机译:恶性胸膜间皮瘤(MPM)仍然是预后不良的癌症。希望实施有效的筛选生物标记物将导致更早的诊断并改善结果。血清测定的可溶性间皮素相关肽(SMRP)已被证明对MPM具有优异的特异性,但敏感性差使其无法用作筛选生物标志物。我们采用了布莱根妇女医院国际间皮瘤计划的一系列MPM患者病例,我们试图确定患者肿瘤中MSLN基因的表观遗传变化是否是SMRP敏感性低的原因。我们在MSLN启动子中确定了CpG甲基化沉默的三个潜在目标区域,其中一个适合亚硫酸氢盐焦磷酸测序,位于转录起始位点上游214 bp。在正常胸膜中,MSLN启动子甲基化明显高于肿瘤组织(p <6.0 x 10 -9)。接下来,我们根据血清SMRP状况比较了病例,并观察到SMRP呈阴性(<1.5 nM)的患者的MSLN甲基化明显高于SMRP呈阳性(p <0.03)的患者。这些结果证明MSLN通常在胸膜中甲基化,并且在大多数肿瘤中甲基化丢失。但是,在一部分肿瘤中甲基化得以保留,这种机制解释了SMRP测定的敏感性差。这些结果可能会导致其他生物标志物靶标,这些靶标将解决SMRP测定法灵敏度低的问题,并允许对暴露人群进行筛查。

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