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 69 publications

(52 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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“…A somatic LINE-1 insertion in the APC gene, together with a point mutation in the second APC allele, was recently shown to initiate colorectal tumorigenesis through the classic two-hit CRC pathway [ 73 ]. The LINE-1 hypomethylation status of circulating cell-free DNA in plasma could be used as a potential biomarker for CRC, particularly for the early stage form [ 74 ].…”

Section: Molecular Biomarkersmentioning

confidence: 99%

Colorectal Cancers: An Update on Their Molecular Pathology

Inamura

2018

Cancers

147

108

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Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed.

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

Cited by 69 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

Colorectal Cancers: An Update on Their Molecular Pathology

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

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