Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma – An external validation study

Henriksen, Stine Dam; Stubbe, Benjamin Emil; Madsen, Poul Thøis; Johansen, Julia S.; Jensen, Benny Vittrup; Hansen, Carsten Palnæs; Johansen, Martin Berg; Pedersen, Inge Søkilde; Krarup, Henrik; Thorlacius-Ussing, Ole

doi:10.1016/j.pan.2021.05.003

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…Recent studies have begun to evaluate the utility of cfDNA for pancreatic cancer detection. Henriksen et al, 33 targeted a handful of specific genes. Others, based on meta‐analysis by the Visser et al, 34 have used cfDNA obtained from pancreatic juice.…”

Section: Discussionmentioning

confidence: 99%

Precision oncology: Artificial intelligence, circulating cell‐free DNA, and the minimally invasive detection of pancreatic cancer—A pilot study

Bahado‐Singh,

Turkoglu,

Aydas

et al. 2023

Cancer Medicine

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BackgroundPancreatic cancer (PC) is among the most lethal cancers. The lack of effective tools for early detection results in late tumor detection and, consequently, high mortality rate. Precision oncology aims to develop targeted individual treatments based on advanced computational approaches of omics data. Biomarkers, such as global alteration of cytosine (CpG) methylation, can be pivotal for these objectives. In this study, we performed DNA methylation profiling of pancreatic cancer patients using circulating cell‐free DNA (cfDNA) and artificial intelligence (AI) including Deep Learning (DL) for minimally invasive detection to elucidate the epigenetic pathogenesis of PC.MethodsThe Illumina Infinium HD Assay was used for genome‐wide DNA methylation profiling of cfDNA in treatment‐naïve patients. Six AI algorithms were used to determine PC detection accuracy based on cytosine (CpG) methylation markers. Additional strategies for minimizing overfitting were employed. The molecular pathogenesis was interrogated using enrichment analysis.ResultsIn total, we identified 4556 significantly differentially methylated CpGs (q‐value < 0.05; Bonferroni correction) in PC versus controls. Highly accurate PC detection was achieved with all 6 AI platforms (Area under the receiver operator characteristics curve [0.90–1.00]). For example, DL achieved AUC (95% CI): 1.00 (0.95–1.00), with a sensitivity and specificity of 100%. A separate modeling approach based on logistic regression‐based yielded an AUC (95% CI) 1.0 (1.0–1.0) with a sensitivity and specificity of 100% for PC detection. The top four biological pathways that were epigenetically altered in PC and are known to be linked with cancer are discussed.ConclusionUsing a minimally invasive approach, AI, and epigenetic analysis of circulating cfDNA, high predictive accuracy for PC was achieved. From a clinical perspective, our findings suggest that that early detection leading to improved overall survival may be achievable in the future.

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Section: Discussionmentioning

confidence: 99%

Precision oncology: Artificial intelligence, circulating cell‐free DNA, and the minimally invasive detection of pancreatic cancer—A pilot study

Bahado‐Singh,

Turkoglu,

Aydas

et al. 2023

Cancer Medicine

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“…In 2021, an external validation of their previously published diagnostic prediction model ( BMP3 , RASSF1A , BNC1 , MESTv2 , TFPI2 , APC , SFRP1 and SFRP2 ) for PDAC [ 75 ] was performed by these researchers, also examining the additional effect of CA 19 − 9 serum on the predictive performance of the diagnostic test [ 86 ]. Results from MSP of the initial 28-gene panel on cfDNA samples from 346 PDAC (stage I-IV) and 25 chronic pancreatitis patients showed a higher number of hypermethylated genes in PDAC patients compared to chronic pancreatitis patients (8.11 vs. 5.60).…”

Section: Analysis Of Cfdna Methylation Studies In Pancreatic Cancermentioning

confidence: 99%

Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects

García-Ortiz,

Cano-Ramírez,

Toledano-Fonseca

et al. 2023

Biomark Res

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Pancreatic cancer is one of the most challenging cancers due to its high mortality rates. Considering the late diagnosis and the limited survival benefit with current treatment options, it becomes imperative to optimize early detection, prognosis and prediction of treatment response. To address these challenges, significant research efforts have been undertaken in recent years to develop liquid-biopsy-based biomarkers for pancreatic cancer. In particular, an increasing number of studies point to cell-free DNA (cfDNA) methylation analysis as a promising non-invasive approach for the discovery and validation of epigenetic biomarkers with diagnostic or prognostic potential. In this review we provide an update on recent advancements in the field of cfDNA methylation analysis in pancreatic cancer. We discuss the relevance of DNA methylation in the context of pancreatic cancer, recent cfDNA methylation research, its clinical utility, and future directions for integrating cfDNA methylation analysis into routine clinical practice.

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“…A genome-wide methylation study has demonstrated that hypermethylation of the SST gene can be detected in cfDNA across all stages of PDA development, with a sensitivity of 89% for PDA diagnosis [ 46 ]. Recently, multiple panels with reliable diagnostic accuracy have been reported for distinguishing PDA from HC or CP [ 42 , 44 , 45 , 56 ]. In one study using a 28-gene promoter panel, the number of methylated genes in the PDA group (8.41 vs. 4.74, p < 0.001) was significantly higher than that in the non-cancer group (HC + CP + acute pancreatitis).…”

Section: Detection Of Cfdna In Pdamentioning

confidence: 99%

Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time?

Sheel

Addison

Nuguru

et al. 2022

Cancers

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Cell-free DNA (cfDNA) testing currently does not have a significant role in PDA management: it is insufficient to diagnose PDA, and its use is primarily restricted to identifying targetable mutations (if tissue is insufficient or unavailable). cfDNA testing has the potential to address critical needs in PDA management, such as pre-operative risk stratification (POR), prognostication, and predicting (and monitoring) treatment response. Prior studies have focused primarily on somatic mutations, specifically KRAS variants, and have shown limited success in addressing prognosis and POR. Recent studies have demonstrated the importance of other less prevalent mutations (ERBB2 and TP53), but no studies have provided reliable mutation panels for clinical use. Methylation aberrations in cfDNA (epigenetic markers) in PDA have been relatively less explored. However, early evidence has suggested they offer diagnostic and, to some extent, prognostic value. The inclusion of epigenetic markers of cfDNA adds another dimension to genomic testing and may open new therapeutic avenues beyond addressing critical areas of need in PDA treatment. For cfDNA to substantially influence PDA management, concerted efforts are required to include less frequent mutations and epigenetic markers. Furthermore, relying on KRAS mutations for PDA management will always be inadequate.

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Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma – An external validation study

Cited by 5 publications

References 31 publications

Precision oncology: Artificial intelligence, circulating cell‐free DNA, and the minimally invasive detection of pancreatic cancer—A pilot study

Precision oncology: Artificial intelligence, circulating cell‐free DNA, and the minimally invasive detection of pancreatic cancer—A pilot study

Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects

Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time?

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