Henriksen Stine D, Stubbe Benjamin E, Madsen Poul H, Johansen Julia S, Jensen Benny V, Hansen Carsten P, Johansen Martin N, Pedersen Inge S, Krarup Henrik, Thorlacius-Ussing Ole
Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark.
Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark.
Pancreatology. 2021 May 8. doi: 10.1016/j.pan.2021.05.003.
We recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9.
Patients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort.
Patients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70-8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42-6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69-0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89-0.96) in the primary study and 0.85 (95% CI 0.79-0.91) in the validation study.
In this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.
我们最近基于浆细胞游离（cf）DNA中8个选定基因的启动子高甲基化鉴定了一种诊断预测模型，该模型作为胰腺导管腺癌（PDAC）的诊断生物标志物显示出了有前景的结果。本研究的目的是在外部患者队列中验证这种生物标志物谱，并检验血清CA 19-9的任何额外作用。
纳入了PDAC患者（n = 346，I-IV期）和慢性胰腺炎患者（n = 25）。对血清cfDNA样本进行了28个基因panel的甲基化特异性PCR。在这个外部患者队列中单独验证了先前开发的诊断预测模型（年龄>65岁、BMP3、RASSF1A、BNC1、MESTv2、TFPI2、APC、SFRP1和SFRP2），并将其与血清CA 19-9联合验证。
与慢性胰腺炎患者（平均5.60，95%CI 4.42-6.78，p = 0.011）相比，PDAC患者的高甲基化基因数量更多（平均8.11，95%CI 7.70-8.52）。诊断预测模型的验证得出AUC为0.77（95%CI 0.69-0.84）。在初步研究中，血清CA 19-9与我们的检测方法联合使用的AUC为0.93（95%CI 0.89-0.96），在验证研究中为0.85（95%CI 0.79-0.91）。
在这项验证研究中，与慢性胰腺炎相比，PDAC与血清cfDNA中更高数量的高甲基化基因相关。在初步研究和验证研究中，我们的诊断检测均优于单独血清CA 19-9的预测价值。我们的检测方法与CA 19-9联合使用可能作为PDAC临床上有用的诊断生物标志物。
