Analysis of Fecal DNA Methylation to Detect Gastrointestinal Neoplasia

Nagasaka, Takeshi; Tanaka, Noriaki; Cullings, Harry M.; Sun, Dawei; Sasamoto, Hiromi; Uchida, Terukazu; Koi, Minoru; Nishida, Naoshi; Naomoto, Yoshio; Boland, C. Richard; Matsubara, Nagahide; Goel, Ajay

doi:10.1093/jnci/djp265

Cited by 115 publications

(78 citation statements)

References 47 publications

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“…SFRP2 methylation has previously been reported in breast, bladder, colon, liver, lung, esophagus, stomach cancer and leukemia. Although detection of SFRP2 methylation in fecal DNA has been shown to be a marker for colorectal cancer and for detection of colorectal polyps (20)(21)(22), in breast cancer SFRP2 methylation was not associated with clinical patient outcome or other clinicopathologic factors, but loss of SFPR2 protein expression was weakly linked to poor patient overall survival (23). Overexpression of SFRP2 in mammary cells leads to inhibition in cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiling of CpG Islands in Breast Cancer Identifies Novel Genes Associated with Tumorigenicity

et al. 2011

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Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P ¼ 0.001), tumor relapse (P ¼ 0.035), and lymph node metastasis (P ¼ 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets. Cancer Res; 71(8); 2988-99. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiling of CpG Islands in Breast Cancer Identifies Novel Genes Associated with Tumorigenicity

et al. 2011

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“…A new and promising strategy for the noninvasive diagnosis of colorectal cancer is based on the analysis of DNA from exfoliated cells excreted in stool (9,10,12). Results comparing stool genomic DNA analysis with the nonrehydrated Hemoccult II FOBT test in a large prospective screening cohort showed higher sensitivity in detecting all cancers, and comparable specificity (26).…”

Section: Discussionmentioning

confidence: 99%

“…Although the majority of studies published on this subject offer somewhat preliminary data, the biological rationale for such a diagnostic procedure seems very promising (9)(10)(11)(12). Indeed, although bleeding is an intermittent and largely unspecific event, cellular exfoliation is a continuous process, which could thus improve test sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Fecal DNA for Noninvasive Diagnosis of Colorectal Cancer in Immunochemical Fecal Occult Blood Test–Positive Individuals

Calistri¹,

Rengucci²,

Casadei-Gardini³

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: We aimed to define the potential of the fecal DNA assay as an alternative or in addition to the currently used immunochemical fecal occult blood test (iFOBT) for the early diagnosis of colorectal cancer.Methods: A total of 560 individuals aged 50 to 69 years with a positive iFOBT were recruited from an Italian FOBT regional screening program. Twenty-six were diagnosed with adenocarcinoma, 264 with high-risk adenoma, and 54 with low-risk adenoma, whereas 216 subjects did not have premalignant or malignant lesions. Fecal DNA integrity was analyzed blindly by the fluorescence long DNA (FL-DNA) test.Results: iFOBT and FL-DNA were largely independent variables (rs = 0.036, P = 0.42), with values ranging from 101 to 5,826 ng/mL and from 0 to 515 ng, respectively. Median values of both variables were significantly higher in cancer patients than in patients with noncancerous lesions or in healthy individuals. Moreover, iFOBT and FL-DNA values were individually associated with a number of pathologic parameters. Sequential use of the diagnostic iFOBT and FL-DNA methods showed that fecal DNA provided more accurate diagnostic information and was able to identify subgroups at different risk of cancer in iFOBT-positive individuals.Conclusions: A combined approach based on FL-DNA and iFOBT evaluation could help to better identify colorectal cancers and to determine a patient's risk of harboring a preneoplastic or neoplastic lesion. Further evaluation in a screening setting is needed to confirm this hypothesis.Impact: Fecal DNA could be a useful tool to better predict cancer risk in FOBT-positive individuals. Cancer

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“…[8][9][10][11][12] Expression of RASSF2 was found to be an independent prognostic factor in gastric cancer patients 10 and RASSF2 methylation could be detected in fecal DNA from patients with gastrointestinal tumors. 13 In functional terms RASSF2 is a novel pro-apoptotic effector of K-Ras and acts as a tumor suppressor gene.…”

Section: Methodsmentioning

confidence: 99%

RASSF2methylation is a strong prognostic marker in younger age patients with Ewing sarcoma

et al. 2013

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Analysis of Fecal DNA Methylation to Detect Gastrointestinal Neoplasia

Cited by 115 publications

References 47 publications

Genome-Wide DNA Methylation Profiling of CpG Islands in Breast Cancer Identifies Novel Genes Associated with Tumorigenicity

Genome-Wide DNA Methylation Profiling of CpG Islands in Breast Cancer Identifies Novel Genes Associated with Tumorigenicity

Fecal DNA for Noninvasive Diagnosis of Colorectal Cancer in Immunochemical Fecal Occult Blood Test–Positive Individuals

RASSF2methylation is a strong prognostic marker in younger age patients with Ewing sarcoma

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