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Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.
To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.
Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).
A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.
To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.
Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).
A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.
摘要：
目的：胰腺导管腺癌（PDAC）通常诊断为晚期。当可以采用治愈性治疗时,液体活检方法可以促进早期PDAC的检测。
方法：为了评估训练中的循环标记区分，测试和验证患者队列(总共n=426名患者)，在PDAC病例和慢性胰腺炎患者中测量血浆标志物，结直肠癌(CRC),和健康的控制。使用CA19-9作为锚标记，对包含61个CpG位点的9个基因座的两个蛋白质标记（TIMP1，LRG1）和无细胞DNA（cfDNA）胰腺特异性甲基化进行了测量。
结果：比较甲基化组分析确定了胰腺外分泌DNA中差异甲基化的9个位点。在训练集中(n=124名患者)，cfDNA甲基化标记区分PDAC与健康和CRC对照。在86个早期PDAC和86个匹配的健康对照的测试集中，CA19-9的受试者工作特征曲线下面积（AUC）为0.88（95％CI0.83至0.94），通过添加TIMP1增加（AUC0.92；95%CI0.88至0.96；p=0.06），LRG1(AUC0.92;95%CI0.88至0.96;p=0.02)或9个位点的外分泌胰腺特异性cfDNA甲基化标记(AUC0.92;95%CI0.88至0.96;p=0.02)。在40个早期PDAC和40个匹配的健康对照的验证集中，与单独使用CA19-9(AUC0.82;95%CI0.72~0.92)相比,包括CA19-9,TIMP1和9-基因座cfDNA甲基化组的组合组具有更大的鉴别(AUC0.86,95%CI0.77~0.95).
结论：对于早期PDAC，与单独使用CA19-9相比，包括蛋白质和甲基化cfDNA在内的一组循环标志物的组合增加了辨别。
方法：为了评估训练中的循环标记区分，测试和验证患者队列(总共n=426名患者)，在PDAC病例和慢性胰腺炎患者中测量血浆标志物，结直肠癌(CRC),和健康的控制。使用CA19-9作为锚标记，对包含61个CpG位点的9个基因座的两个蛋白质标记（TIMP1，LRG1）和无细胞DNA（cfDNA）胰腺特异性甲基化进行了测量。
结果：比较甲基化组分析确定了胰腺外分泌DNA中差异甲基化的9个位点。在训练集中(n=124名患者)，cfDNA甲基化标记区分PDAC与健康和CRC对照。在86个早期PDAC和86个匹配的健康对照的测试集中，CA19-9的受试者工作特征曲线下面积（AUC）为0.88（95％CI0.83至0.94），通过添加TIMP1增加（AUC0.92；95%CI0.88至0.96；p=0.06），LRG1(AUC0.92;95%CI0.88至0.96;p=0.02)或9个位点的外分泌胰腺特异性cfDNA甲基化标记(AUC0.92;95%CI0.88至0.96;p=0.02)。在40个早期PDAC和40个匹配的健康对照的验证集中，与单独使用CA19-9(AUC0.82;95%CI0.72~0.92)相比,包括CA19-9,TIMP1和9-基因座cfDNA甲基化组的组合组具有更大的鉴别(AUC0.86,95%CI0.77~0.95).
结论：对于早期PDAC，与单独使用CA19-9相比，包括蛋白质和甲基化cfDNA在内的一组循环标志物的组合增加了辨别。
