Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Surgery, Aidu Chuo Hospital, Aizuwakamatsu, Japan.
Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Pancreatology. 2023 Mar;23(2):218-226. doi: 10.1016/j.pan.2023.01.006. Epub 2023 Jan 13.
BACKGROUND/OBJECTIVES: Screening patients with intraductal papillary mucinous neoplasms (IPMN) has the primary goal of identifying potentially curable noninvasive precursors. We aimed to evaluate the diagnostic impact of genetic and epigenetic biomarkers in the presence of noninvasive precursors.
Mutated KRAS/GNAS and methylated SOX17/TBX15/BMP3/TFPI2 DNA were assessed by droplet digital PCR in a discovery cohort of 70 surgically aspirated cyst fluids, and diagnostic performances for differentiating high-grade dysplasia (HGD) from low-grade dysplasia (LGD) was evaluated. We then tested these markers using an independent test cohort consisting of 156 serially collected pancreatic juice samples from 30 patients with IPMN.
Mutated KRAS and GNAS are specific for IPMNs but are not helpful for the prediction of histological grades. Cyst fluids from IPMN with HGD showed higher methylation levels of SOX17 (median, 0.141 vs. 0.021; P = 0.086) and TBX15 (median, 0.030 vs. 0.003; P = 0.028) than those with LGD. The combination of all tested markers yielded a diagnostic performance with sensitivity of 69.6%, and specificity of 90.0%. Among the 30 pancreatic juice samples exhibiting the highest abundance of KRAS/GNAS mutations in each patient in the test cohort, patients with histologically proven HGD due to pancreatic resection had a significantly higher prevalence (100% vs. 31%, P = 0.018) and abundance (P = 0.037) of methylated TBX15 than those without cytohistological diagnosis undergoing surveillance.
A simultaneous and sequential combination of mutated and methylated DNA markers in pancreatic cyst fluid and juice sample markers can help detect noninvasive pancreatic precursor neoplasms.
背景/目的：对患有导管内乳头状黏液性肿瘤（IPMN）的患者进行筛查，主要目的是识别具有潜在可治愈性的非浸润性前体。我们旨在评估存在非浸润性前体时遗传和表观遗传生物标志物的诊断影响。
通过液滴数字 PCR 检测 70 例手术抽吸的囊液中突变的 KRAS/GNAS 和甲基化的 SOX17/TBX15/BMP3/TFPI2 DNA，并评估其用于区分高级别异型增生（HGD）和低级别异型增生（LGD）的诊断性能。然后，我们使用包含 30 例 IPMN 患者连续采集的 156 份胰液样本的独立测试队列来测试这些标志物。
突变的 KRAS 和 GNAS 是 IPMN 的特异性标志物，但对预测组织学分级没有帮助。HGD 型 IPMN 的囊液中 SOX17（中位数，0.141 比 0.021；P=0.086）和 TBX15（中位数，0.030 比 0.003；P=0.028）的甲基化水平较高。所有测试标志物的组合具有 69.6%的敏感性和 90.0%的特异性。在测试队列中每位患者 KRAS/GNAS 突变丰度最高的 30 份胰液样本中，因胰腺切除术而具有组织学证实的 HGD 的患者，其 TBX15 甲基化的发生率（100%比 31%，P=0.018）和丰度（P=0.037）显著更高。
胰腺囊液和胰液样本标志物中突变和甲基化 DNA 标志物的同时和序贯组合可有助于检测非浸润性胰腺前体肿瘤。
