Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer

Shan, Ming; Yin, Huizi; Li, Junnan; Li, Xiaobo; Wang, Dong; Su, Yonghui; Niu, Ming; Zhong, Zhenbin; Ji, Wang; Zhang, Xianyu; Kang, Wenli; Pang, Da

doi:10.18632/oncotarget.7608

Cited by 90 publications

(82 citation statements)

References 39 publications

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“…Single-CTC methylation analysis was recently demonstrated by Huang and colleagues, indicating at a gross level that DNA was hypomethylated and RNA was hypermethylated [162,163]. Along similar lines, methylation patterns in ctDNA has been used to identify tissue-specific cell death [164], and ctDNA detection of aberrant promoter methylation in a six-gene panel has been used for diagnosing breast cancer [165]. Con current multiomics analysis of single CTCs in a highly automated and multiplexed fashion using microfluidics and barcoding technology could augment lineage tracing and dissection of the genetic and epigenetic contributions to CTC cell state and dynamics (via the transcriptome readout) [166].…”

Section: Conclusion and Future Perspectivementioning

confidence: 88%

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

Hwang

Miyamoto

2016

Biomark. Med.

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The rapidly growing array of therapeutic options in cancer requires informative biomarkers to guide the rational selection and precision application of appropriate therapies. Circulating biomarkers such as circulating tumor cells have immense potential as noninvasive, serial 'liquid biopsies' that may be more representative of the complete spectrum of a patient's individual malignancy than spatially and temporally restricted tumor biopsies. In this review, we discuss the current state-of-the-art in the isolation and molecular characterization of circulating tumor cells as well as their utility in a wide range of clinical applications such as prognostics, treatment monitoring and identification of novel therapeutic targets and resistance mechanisms to enable real-time adjustments in the clinical management of cancer. The evolving landscape of cancer therapy creates an urgent need for minimally invasive biomarkers to facilitate early detection, prognosis and prediction of therapeutic response and resistance to enable highly adaptable, real-time precision therapy [1]. The conventional gold standard of using single biopsies of the primary tumor to inform all downstream therapeutic decisions may no longer be adequate given increasing evidence of significant spatial and temporal hetero geneity in tumors [2], especially when placed under the selection pressure of various treatments. Moreover, serial biopsies are often impractical, morbid and technically challenging.In this review, we focus on the emerging role of circulating tumor cells (CTCs), which can be serially obtained from minimally invasive blood draws or 'liquid biopsies'. CTCs are cancer cells that have been shed into the peripheral circulation from primary or metastatic tumors [3,4]. The first reported observation of CTCs was in 1869 by Australian pathologist Thomas Ashworth at the autopsy of a patient with metastatic cancer [5]. By comparing the morphology of circulating cells with those from different cancerous lesions, Ashworth came to the prescient conclusion that 'cells identical with those of the cancer itself being seen in the blood may tend to throw some light upon the mode of origin of multiple tumors existing in the same person' [5]. Indeed, molecular analyses of CTCs may be superior to individual tumor biopsies because these circulating cells likely provide a sampling of different regions of the primary tumor as well as metastatic deposits, and therefore are more likely to capture the genetic heterogeneity of a patient's cancer.While cell-free circulating tumor DNA (ctDNA) is an important, complementary biomarker to CTCs, it has been reviewed extensively elsewhere and will not be discussed in this review [4,6]. Moreover, although ctDNA may in some cases be more reliably [7], they are largely limited to genomic mutational analysis. In contrast, CTC analysis can provide a wealth of other information including cell morphology, immunocytochemical phenotype, presence of important epitopes, presence of multiple mutations within a single cell to decode ...

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Section: Conclusion and Future Perspectivementioning

confidence: 88%

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

Hwang

Miyamoto

2016

Biomark. Med.

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“…It is worth noting that diagnostic and prognostic value of ctDNA has been discussed for different subtypes of breast cancer, including triple-negative breast cancer (TNBC) [105], luminal breast cancer, [78] and HER2-positive breast cancer [109]. …”

Section: Discussionmentioning

confidence: 99%

“…Methylation changes in MAL, SFRP1 [38], RASSF1A [38,78], SFN, P16, PCDHGB7, HOXD13, hMLH1 [78], ERβ and RARβ2 [79] have also been identified in ctDNA fragments of breast cancer patients.…”

Section: Genetic and Epigenetic Profilesmentioning

confidence: 99%

Analysis of circulating tumor DNA in breast cancer as a diagnostic and prognostic biomarker

Rohanizadegan

2018

Cancer Genetics

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Despite all the advances in diagnosis and treatment of breast cancer, a large number of patients suffer from late diagnosis or recurrence of their disease. Current available imaging modalities do not reveal micrometastasis and tumor biopsy is an invasive method to detect early stage or recurrent cancer, signifying the need for an inexpensive, non-invasive diagnostic modality. Cell-free tumor DNA (ctDNA) has been tried for early detection and targeted therapy of breast cancer, but its diagnostic and prognostic utility is still under investigation. This review summarizes the existing evidence on the use of ctDNA specifically in breast cancer, including detection methods, diagnostic accuracy, role in genetics and epigenetics evaluation of the tumor, and comparison with other biomarkers. Current evidence suggests that increasing levels of ctDNA in breast cancer can be of significant diagnostic value for early detection of breast cancer although the sensitivity and specificity of the methods is still suboptimal. Additionally, ctDNA allows for characterizing the tumor in a non-invasive way and monitor the response to therapy, although discordance of ctDNA results with direct biopsy (i.e. due to tumor heterogeneity) is still considered a notable limitation.

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Section: Introductionmentioning

confidence: 99%

“…Furthermore, Bayoglu et al (14) reported that increased CDKN2A gene expression in artery plaques may increase the risk of atherosclerosis and contribute to the development of carotid artery stenosis. Although methylation-induced CDKN2A downregulation is observed in multiple human cancer types (15)(16)(17), few studies have evaluated the epigenetic role of CDKN2A in CHD.CDKN2B gene lies adjacent to CDKN2A, and the protein encoded by this gene is associated with controlling cell cycle CDKN2A and CDKN2B methylation in coronary heart disease cases and controls …”

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confidence: 99%

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

Zhong

Chen

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation-specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non-CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73±5.88 vs. 62.62±5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26±5.48 vs. 58.33±7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation. IntroductionCoronary heart disease (CHD) is a complex chronic disease that is caused by an imbalance between blood supply and demand in myocardium. Various environmental and genetic factors are known to contribute to onset and development of CHD (1). As of 2010, CHD was the leading cause of mortality globally, resulting in over 7 million cases of mortality (2). Therefore, association studies for CHD biomarkers have been performed worldwide (3-5) for future forefront diagnostics for the early assessment of cardiac risks.The genetic locus at chromosome 9p21 has been demonstrated to be strongly associated with the risk of CHD (6,7). Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes both encode putative regulators of cyclin-dependent kinases on chromosome 9p21. Genome-wide association studies have identified that some CDKN2A or CDKN2B genetic variants are susceptible to CHD (8-10). As recently reported, many human diseases, including cardiovascular disease, could be influenced by aberrant DNA methylation modification (11). Aberrant methylation of cytosine-phosphate-guanine (CpG) islands in gene promoters is associated with transcription silencing and activity (3). However, the exact role of CDKN2A and CDKN2B methylation in cardiovascular system has not yet been fully elucidated.CDKN2A gene is involved in the regulation of cell proliferation, cell aging and apoptosis (12). However, a bidirectional role of CDKN2A gene expression has been reported in previous studies. Knösel et al (13) reported...

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Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer

Cited by 90 publications

References 39 publications

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

Analysis of circulating tumor DNA in breast cancer as a diagnostic and prognostic biomarker

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

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