Diagnostic potential of hypermethylation of the cysteine dioxygenase 1 gene (CDO1) promoter DNA in pancreatic cancer

Abstract

DNA markers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed for detection of minimally invasive disease. The epigenetic relevance of the cysteine dioxygenase 1 gene (CDO1) has been never investigated in PDAC. Three studies, including cellular experiments, tissue validation, and pilot testing for pancreatic cytology, were carried out. Promoter DNA methylation value (MV) of CDO1 was quantified by quantitative methylation‐specific PCR. CDO1 expression was consistent with its promoter DNA methylation in 7 PDAC cell lines. In 160 retrospectively collected primary PDAC tumor tissues, MV was significantly higher compared to the corresponding noncancerous pancreas (area under the receiver operating characteristic curve [AUC] = 0.97, P < .0001), and CDO1 hypermethylation was highly specific to PDAC tumor tissues. CDO1 hypermethylation group (MV over 19) was significantly associated with diverse prognostic factors in PDAC. Surprisingly, it was significantly higher in prospectively collected PDAC cytology samples (n = 37), including both pancreatic juice (n = 12) and endoscopic ultrasound‐fine needle aspiration (EUS‐FNA) cytology (n = 25) compared to pancreatic benign diseases (AUC = 0.96, P < .0001). Detection of PDAC was confirmed by DNA testing in 35 of 37 patients (95% sensitivity); thus, it was more sensitive than cytology (33%) or EUS‐FNA cytology (88%). Promoter DNA methylation of CDO1 is extremely specific for PDAC tumors, and accumulates with PDAC tumor progression. It could be a definitive diagnostic marker of PDAC in pancreatic juice or EUS‐FNA cytology.

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

“…CpG island methylation in promoters is frequently associated with gene silencing during tumorigenesis, providing an alternative mechanism to mutations by which tumor suppressor genes may be inactivated within a cancer cell [ 17 , 18 ]. In our exploratory cohort, as well as in other studies, the Tumor Suppressor Genes (TSGs) NPTX2 (Neuronal Pentraxin 2), CDO1 (Cysteine Dioxygenase Type 1), TFPI2 (Tissue Factor Pathway Inhibitor 2), SFRP1 (Secreted Frizzled Related Protein 1), SFRP2 (Secreted Frizzled Related Protein 2), PENK (Proenkephalin) and FOXE1 (Forkhead box E1) had a remarkable hypermethylation pattern in the PDAC group [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Identification of mRNAs and lncRNAs Involved in the Regulation of Follicle Development in Goat

“…In addition, CDO1, NTRK1, MRO, and TC2N (the other two genes in the list of 43 genes) were all upregulated in large follicles and might therefore potentially participate in the regulation of follicular maturation in goats, which have not been identified in the context of follicular development and maturation before (as far as we know). The protein encoded by CDO1 affects mitochondrial function by converting cystine to cysteine sulfamic acid and inhibits the production of glutathione to promote apoptosis, and it has been used as a diagnostic marker in a variety of cancers (Kang et al, 2019;Nishizawa et al, 2019). The NTRK1 protein was found to facilitate follicle assembly and early follicular development in the mouse ovary (Kerr et al, 2009).…”

Dipeptidyl peptidase like 6 promoter methylation is a potential prognostic biomarker for pancreatic ductal adenocarcinoma

“…Promoter methylation of PCDH10 was observed in cancer cells, and the expression of PCDH10 could be restored by 5-aza-2′-deoxycytidine [ 17 ]. For certain genes such as CDO1 , promoter methylation could be used as a diagnostic biomarker, and methylation of the ZNF671 promoter could predict survival [ 3 , 20 ].…”