LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer

Nagai, Yoshinori; Sunami, Eiji; Yamamoto, Yasutake; Hata, Keisuke; Okada, Satoshi; Murono, Koji; Yasuda, Koji; Otani, Kensuke; Nishikawa, Takeshi; Tanaka, Toshiaki; Kiyomatsu, Tomomichi; Kawai, Kazushige; Nozawa, Hiroaki; Ishihara, Soichiro; Hoon, Dave S. B.; Watanabe, Toshiaki

doi:10.18632/oncotarget.14439

Cited by 64 publications

(46 citation statements)

References 42 publications

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“…2 ). The cfDNA yield in the control group did not show any overt deviation from control cohorts described in other studies 26 , 37 . On the other hand, the cfDNA levels in the adenoma group were lower than previously reported 26 .…”

Section: Resultssupporting

confidence: 43%

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity

et al. 2018

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Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients’ plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies.

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Section: Resultssupporting

confidence: 43%

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity

et al. 2018

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“…LINE-1 hypomethylation in ctDNA was linked to poor overall survival in diffuse large B cell lymphoma and to surrogate biomarkers for neuroblastoma tumor burden (28,29). As an additional evidence of its clinical bene t, LINE-1 hypomethylation is described as a blood biomarker to detect colorectal cancer, particularly in the early stages of the disease (30).…”

Section: Discussionmentioning

confidence: 99%

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

Misawa

Yamada

Mima

et al. 2020

Preprint

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Background: New biomarkers are urgently needed to improve personalized treatment approaches for head and neck squamous cell carcinoma (HNSCC). Global DNA hypomethylation has wide-ranging functions in multistep carcinogenesis, and the hypomethylation of long interspersed nucleotide element-1 (LINE-1) has been generally considered to be related with increased retrotransposon activity and induced genome instability. However, little information is available regarding LINE-1 hypomethylation and its prognostic implications in HNSCC. Methods: In this study, we analyzed LINE-1 hypomethylation levels in a well-characterized dataset of 317 matched pairs of HNSCC tissues and oral cavity cancer (OCC) circulating tumor DNA (ctDNA) using quantitative real-time methylation and unmethylation PCR. This analysis was performed according to various clinical characteristics and prognostic implications. Results: Our results demonstrated that LINE-1 hypomethylation levels were significantly higher in HNSCC tissues than in corresponding normal tissues from the same individuals (P < 0.001). Univariate analysis revealed that high levels of LINE-1 hypomethylation were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038), whereas multivariate analysis demonstrated that it is a significant independent prognostic factor for DFS (hazard ratio: 2.10, 95% confidence interval: 1.02–4.36; P = 0.045). Moreover, patients with high LINE-1 hypomethylation levels exhibited the greatest decrease in 5-hydroxymethylcytosine (5-hmC) levels and increase in tumor-suppressor gene methylation index (P = 0.006 and P < 0.001, respectively). Further ctDNA studies also showed that LINE-1 hypomethylation had high predictive ability for OCC. Conclusions: LINE-1 hypomethylation is associated with a higher risk of early OCC relapse, and is hence, a potential predictive biomarker for OCC. Furthermore, 5-hmC levels also exhibited predictive potential in OCC, based on its inverse correlation with LINE-1 hypomethylation levels. LINE-1 hypomethylation analysis, therefore, has applications in determining patient prognosis and real-time surveillance for disease recurrence, and could serve as an alternative method for OCC screening.

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“…Aberrant changes in DNA methylation are very promising as these tumor-derived changes might also be monitored in body fluids or stool specimens. Global hypo- and hypermethylation can also be assessed in circulating cell-free DNA isolated from the plasma of CRC patients, thus revealing a novel and low-invasive diagnostic biomarker that is also relevant for early-stage [ 181 ].…”

Section: Clinical Applications Of Dna Methylation Profilingmentioning

confidence: 99%

Methylation-Based Therapies for Colorectal Cancer

Červená

Siskova

Büchler

et al. 2020

Cells

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Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

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LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer

Cited by 64 publications

References 42 publications

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

Methylation-Based Therapies for Colorectal Cancer

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