Methylated circulating tumor DNA in blood: power in cancer prognosis and response

Warton, Kristina; Mahon, Kate; Samimi, Goli

doi:10.1530/erc-15-0369

Cited by 148 publications

(110 citation statements)

References 95 publications

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“…To date, a handful of "proof of concept" studies have emerged, outlining the basis of such methods in breast and colorectal cancers. [47][48][49] Given that colorectal cancer initially develops from colon polyps, and that epigenetic modifications are believed to be precursors of cancer formation, 5 another step would be testing GSDME methylation in polyps to assess its potential as an early biomarker for colorectal cancer. Considering the models' robustness and the low number of predictor probes needed, the answer might ultimately lie in the use of GSDME methylation in liquid biopsies as a sensitive, minimally-invasive and cost-effective detection method for colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

et al. 2019

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In addition to its implication in hereditary hearing loss, the Gasdermin E ( GSDME ) gene is also a tumor suppressor involved in cancer progression through programmed cell death. GSDME epigenetic silencing through methylation has been shown in some cancer types, but studies are yet to fully explore its diagnostic/prognostic potential in colorectal cancer on a large‐scale. We used public data from The Cancer Genome Atlas (TCGA) to investigate differences in GSDME methylation and expression between colorectal cancer and normal colorectal tissue, and between left‐ and right‐sided colorectal cancers in 432 samples. We also explored GSDME 's diagnostic capacity as a biomarker for colorectal cancer. We observed differential methylation in all 22 GSDME CpGs between tumor and normal tissues, and in 18 CpGs between the left‐ and right‐sided groups. In the cancer tissue, putative promoter probes were hypermethylated and gene body probes were hypomethylated, while this pattern was inversed in normal tissues. Both putative promoter and gene body CpGs correlated well together but formed distinct methylation patterns with the putative promoter exhibiting the most pronounced methylation differences between tumor and normal tissues. Clinicopathological parameters, excluding age, did not show any effect on CpG methylation. Although the methylation of 5 distinct probes was a good predictor of gene expression, we could not identify an association between GSDME methylation and expression in general. Survival analysis showed no association between GSDME methylation and expression on 5‐year patient survival. Through logistic regression, we identified a combination of 2 CpGs, that can discriminate between cancer and normal tissue with high accuracy (AUC = 0.95) irrespective of age and tumor stage. We also validated our model in 3 external methylation datasets, from the Gene Expression Omnibus database, and similar results were reached. Our results suggest that GSDME is a promising biomarker for the detection of colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

et al. 2019

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“…The ctDNA content varies in different tumor types and stages, and the mutation profiles for individual tumors may vary between patients [30], [70], [71], [72]. Unlike genetic alterations, methylation of ctDNAs is very consistent in cancer patients [14]. The aberrant methylations of ctDNAs have been described and investigated for clinical applications in most cancer types.…”

Section: Plasma Ctdna In the Clinicmentioning

confidence: 99%

Circulating Tumor DNA as Biomarkers for Cancer Detection

Han

Wang

Sun

2017

Genomics, Proteomics &Amp; Bioinformatics

199

163

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Detection of circulating tumor DNAs (ctDNAs) in cancer patients is an important component of cancer precision medicine ctDNAs. Compared to the traditional physical and biochemical methods, blood-based ctDNA detection offers a non-invasive and easily accessible way for cancer diagnosis, prognostic determination, and guidance for treatment. While studies on this topic are currently underway, clinical translation of ctDNA detection in various types of cancers has been attracting much attention, due to the great potential of ctDNA as blood-based biomarkers for early diagnosis and treatment of cancers. ctDNAs are detected and tracked primarily based on tumor-related genetic and epigenetic alterations. In this article, we reviewed the available studies on ctDNA detection and described the representative methods. We also discussed the current understanding of ctDNAs in cancer patients and their availability as potential biomarkers for clinical purposes. Considering the progress made and challenges involved in accurate detection of specific cell-free nucleic acids, ctDNAs hold promise to serve as biomarkers for cancer patients, and further validation is needed prior to their broad clinical use.

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“…In oncology, epigenetic alterations in cancer cells have been linked to increased expression of drug efflux transporters, mediating resistance to chemotherapy. Detection of epigenetically modified DNA in the blood stream can be used for tumor stratification and presents an emerging tool for monitoring treatment efficacy as well as development of drug resistance [8,9]. Moreover, pharmacological modulators of the epigenetic machinery have been successfully used in oncological treatment, mostly as adjuvants to sensitize tumors to standard-of-care chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Lauschke

Milani

Ingelman‐Sundberg

2017

AAPS J

118

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Abstract.Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drugmetabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.

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Methylated circulating tumor DNA in blood: power in cancer prognosis and response

Cited by 148 publications

References 95 publications

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Circulating Tumor DNA as Biomarkers for Cancer Detection

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

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