Promoter hypermethylation in plasma‐derived cell‐free DNA as a prognostic marker for pancreatic adenocarcinoma staging

Abstract

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer

“…TAC1 encodes preprotachykinin-1, which is converted to neurokinin A or substance P (36). Since neurokinin A inhibits cell proliferation in normal cell (37), TAC1 is therefore considered a tumor-suppressor gene, and hypermethylation of the TAC1 CpG island promoter has been observed in various types of cancer, including lung (non-small cell type) cancer (14), colon cancer (15), head and neck cancer (16), uterus cancer (17) and pancreatic cancer (27,28). Patai et al (38) reported that TAC1 promoter is hypermethylated in the precancerous condition of colorectal sessile serrated adenomas.…”

“…Vedeld et al (12) demonstrated that the promoter region of CDO1 in pancreatic cancer, formalin-fixed, paraffin-embedded (FFPe) samples was hypermethylated. Furthermore, Henriksen et al (27,28) reported that the promoter of TAC1 in the plasmatic nucleic acids of patients with pancreatic cancer was hypermethylated, and the promoter of CHFR was not hypermethylated. However, the hypermethylation of these genes promoters in pancreatic cancer tissues was not compared with adjacent non-cancerous pancreatic tissues.…”

“…However, the hypermethylation of these genes promoters in pancreatic cancer tissues was not compared with adjacent non-cancerous pancreatic tissues. whether hypermethylation of these genes is already present in non-cancerous pancreatic tissues remains therefore unclear, as this was not examined by Henriksen et al (27,28). CDO1, TAC1, and CHFR methylation in pancreatic cancer tissues have not been compared with adjacent non-cancerous pancreatic tissues.…”

Identification of a 4‐mRNA metastasis‐related prognostic signature for patients with breast cancer

“…Up to now, the American Joint Committee on Cancer (AJCC) staging system has always been broadly adopted for cancer management, including BC . However, the current TNM Classification method cannot perfectly provide accurate information to predict patients’ prognosis . Then some patients with BC received unnecessary or excessive medication, while others may be faced with recurrence or metastasis due to lack of appropriate treatment .…”

Impact of circulating tumor DNA in hepatocellular and pancreatic carcinomas

“…Methylation analyses of ctDNA that reveal epigenetic alterations with more or less diagnostic and prognostic impact reflect the remarkable heterogeneity in PC patients. CfDNA promotor hypermethylation in plasma or serum could be detected in all stages of PC (Henriksen et al 2017b). Henriksen et al developed a survival prediction model based on plasma-derived cfDNA hypermethylation of a large gene panel that enables the stratification of patients into risk groups (Henriksen et al 2017a).…”