SST gene hypermethylation acts as a pan-cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood-based diagnosis
SST gene hypermethylation acts as a pan-cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood-based diagnosis
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DOI：
10.1002/1878-0261.12684
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发表时间：
2020-04-14
影响因子：
6.6
通讯作者：
Bauer, Andrea S.
中科院分区：
文献类型：
--
作者：
Manoochehri, Mehdi;Wu, Yenan;Bauer, Andrea S.
DNA甲基化异常经常与癌症的发生有关。我们最初的目标是确定与胰腺癌相关的DNA甲基化生物标记物。对胰腺导管腺癌(PDAC)和胰腺内分泌肿瘤的DNA进行了全基因组甲基化研究。在患者样本和胰腺癌细胞系上进行了DNA甲基化模式和伴随的候选基因表达变化的验证。此外，对来自癌症基因组图谱(TCGA)和基因表达总览(GEO)的独立数据进行了验证。最后，使用Droplet数字聚合酶链式反应检测从PDAC患者和无癌献血员的血浆样本中分离的无细胞(Cf)DNA中的DNA甲基化标记。在PDAC和内分泌肿瘤组织中发现SST基因(编码生长抑素)高甲基化并伴随其表达下调，而在慢性胰腺炎(炎症)组织和正常胰腺组织中不存在。恰如其分的是，生长抑素激动剂(奥曲肽)的治疗减少了胰腺癌细胞的细胞增殖和迁移。在受试者工作特征曲线分析中，SST甲基化对组织和血浆样本的诊断性能分别为100%和89%。大量的TCGA和GEO数据证实了PDAC中SST的高甲基化和下调，并在广泛的其他肿瘤实体中显示出类似的效果。SST启动子甲基化是一种在肿瘤组织和液体活检样本中可检测到的敏感和有前景的分子泛癌生物标记物。
Aberrant DNA methylation is often involved in carcinogenesis. Our initial goal was to identify DNA methylation biomarkers associated with pancreatic cancer. A genomewide methylation study was performed on DNA from pancreatic ductal adenocarcinoma (PDAC) and endocrine pancreas tumors. Validation of DNA methylation patterns and concomitant alterations in expression of gene candidates was performed on patient samples and pancreatic cancer cell lines. Furthermore, validation was done on independent data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Finally, droplet digital PCR was employed to detect DNA methylation marks in cell-free (cf) DNA isolated from plasma samples of PDAC patients and cancer-free blood donors. Hypermethylation of the SST gene (encoding somatostatin) and concomitant downregulation of its expression were discovered in PDAC and endocrine tumor tissues while not being present in chronic pancreatitis (inflamed) tissues and normal pancreas. Fittingly, treatment with a somatostatin agonist (octreotide) reduced cell proliferation and migration of pancreatic cancer cells. Diagnostic performance of SST methylation in a receiver operating characteristic curve analysis was 100% and 89% for tissue and plasma samples, respectively. A large body of TCGA and GEO data confirmed SST hypermethylation and downregulation in PDAC and showed a similar effect in a broad spectrum of other tumor entities. SST promoter methylation represents a sensitive and promising molecular, pan-cancer biomarker detectable in tumor tissue, and liquid biopsy samples.