DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Carmona, Francisco javier García; Azuara, Daniel; Berenguer‐Llergo, Antoni; Fernández, Agustín F.; Biondo, Sebastiano; de, Javier; Rodríguez-Moranta, Francisco; Salazar, Ramón; Villanueva, Alberto; Fraga, Mario F.; Guardiola, Jordi; Capellà, Gabriel; Esteller, Manel; Moreno, Vı́ctor

doi:10.1158/1940-6207.capr-12-0501

Cited by 112 publications

(80 citation statements)

References 46 publications

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“…22). Pyrosequencing assays were designed to analyze and validate the results obtained from the WGBS data at intragenic DMRs, and to analyze DNA methylation levels in human breast cancer samples (23). Bisulfite-genomic sequencing (24) was carried out to validate DNA methylation at DMRs overlapping transcription start site-proximal regions.…”

Section: Dna Methylation Analysesmentioning

confidence: 99%

A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells, and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-toepithelial transition. The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of Madin-Darby canine kidney cells undergoing EMT and translated the identified differentially methylated regions to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.

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Section: Dna Methylation Analysesmentioning

confidence: 99%

A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition

et al. 2014

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“…Besides, the AGTR1 promoter methylation is associated with oral squamous cell carcinoma (OSCC) development (12). And AGTR1 was also validated in stool DNA with a high detection sensitivity for noninvasive diagnosis of colorectal cancer (13). In addition, DNA methylation microarray datasets showed that methylation of AGTR1 might be an effective biomarker for NSCLC diagnosis (17).…”

Section: Introductionmentioning

confidence: 99%

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

et al. 2017

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Abstract. Aberrant DNA methylation is associated with non-small cell lung cancer (NSCLC), suggesting that gene promoter methylation may be a potential biomarker for the detection or risk prediction of NSCLC. The present study aimed to evaluate the potential usage of angiotensin II receptor type 1 (AGTR1) methylation in two major pathologic subtypes: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Quantitative methylation-specific polymerase chain reaction was used to investigate the effect of AGTR1 promoter methylation in the tumor and the paired adjacent non-tumor tissue samples from 42 patients with LUSC, and 69 with LUAD. The percentage of methylated reference was calculated and presented as the median (interquartile range 25th-75th percentile). The results of the current study revealed that there was significantly increased AGTR1 promoter methylation in the tumor tissues compared with the paired adjacent non-tumor tissue [97.4 (57.22-130.5) vs. 85 (48.25-123); P=0.024]. Furthermore, higher AGTR1 promoter methylation was observed in patients with LUSC compared with LUAD (odds ratio=2.483; 95% confidence interval=1.125-5.480; P=0.023). Significant differences were identified in AGTR1 methylation between non-tumor and the tumor tissues in LUSC [113.5 (68.33-148.73) vs. 93.04 (45.94-140); P=0.008]. In addition, the Cancer Genome Atlas data of 378 patients with LUSC and 477 with LUAD revealed an inverse correlation between gene expression and the methylation status of AGTR1 promoter.. These data suggest that AGTR1 hypermethylation is a promising biomarker to assist in LUSC detection and diagnosis. IntroductionLung cancer is a kind of malignancy that arises from epithelial cells. It is the leading cause of cancer-related death worldwide (1). There were nearly 1.8 million new patients and caused 159 million deaths in 2012, of which China accounted for more than one third (2). According to the size and appearance of the malignant cells, lung cancer is categorized as non small cell lung cancer (NSCLC) and small cell lung cancer (3). NSCLC represents approximately 85% of lung cancer (4), and it can be further subdivided into large cell carcinoma, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). There are a lot of differences in molecular profiling, characteristics and therapeutic methods between LUAD and LUSC (5).Promoter hypermethylation of the tumor suppressor genes has been recognized as an important factor in inducing oncogenesis (6). For example, SRY-box 17 (SOX17) methylation was found in 60.2% of primary lung cancer samples, and promoter methylation of SOX17 silenced gene expression, leading to the elimination of cell proliferation suppression in lung cancer (7). Identification of specific gene hypermethylation may explain the genomic instability and complexity of NSCLC and provide a basis for targeted therapy or risk prediction. AGTR1 promoter hypermethylation in lung squamouscell carcinoma but not in lung adenocarcinoma

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“…Slit levels dramatically decrease in the midgut of Atg16 WD40 and Rab19 mutant flies, similar to IBD patients with decreased Slit expression due to promoter hypermethylation (Lobatón et al, 2014). Interestingly, Slit promoter hypermethylation in IBD patients is associated with an increased risk of cancer (Carmona et al, 2013). Notably, Atg16 WD40 mutations also lead to an early dysplasia-like gut phenotype in adult flies.…”

Section: Discussionmentioning

confidence: 99%

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

et al. 2017

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Genetic variations of Atg16l1, Slit2 and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine (pre-EE) cells accumulate that fail to differentiate into properly functioning secretory EE cells. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE cell generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling triggers an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domainspecific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.

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DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Cited by 112 publications

References 46 publications

A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition

A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

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