Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

胰腺癌通常在较晚时发现，无法再进行治疗。在这里，我们 与非癌症人群（n  = 243）相比，通过5-羟甲基胞嘧啶（5hmC）对来自PDAC人群（n = 64）的循环无细胞DNA的变化的5-羟甲基胞嘧啶（5hmC）变化，无创检测胰腺导管腺癌（PDAC ） 。羟甲基差在数以千计的基因，最显著的发现与胰腺发育或功能（基因GATA4，GATA6，PROX1，ONECUT1，MEIS2），和发病机制（YAP1，TEAD1，PROX1，IGF1）。PDAC队列中的cfDNA羟甲基基因组富含KRAS激活和TP53失活后通常在PDAC肿瘤中失调的基因。使用基因中5hmC密度构建的正则化回归模型的AUC分别为0.92（发现数据集，n  = 79）和0.92-0.94（两个独立的测试集，n  = 228）。此外，组织来源的5hmC特征可用于对PDAC cfDNA进行分类（AUC = 0.88）。这些发现表明，即使在疾病早期，5hmC的变化也可以对PDAC进行分类。