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Abstract
Screening for colorectal cancer is widely considered a cost effective intervention with strong evidence supporting mortality reduction in the screened population. Despite this, global screening rates remain low, even in developed countries. Blood based screening tests have the potential to overcome resistance to screening, thereby increasing overall participation, and saving lives. Here we review the development of a recently US FDA approved blood based epigenetic screening test for colorectal cancer. The Epi proColon test is based on the Septin 9 (SEPT9) gene promoter methylation status measured in cell free DNA from plasma. While the assessment of DNA methylation has been practiced in laboratories for some time, the approved test provides a standardized and kitted method for isolation of cell free DNA from plasma, reagents and methods for bisulfite conversion and purification of converted DNA (bisDNA) in preparation for DNA methylation analysis by real time PCR. This enables broad dissemination of DNA methylation based testing to laboratories approved to perform standard molecular diagnostics. In clinical trials, the approved Epi proColon test had sensitivity for colorectal cancer of 68-72%, comparable to commonly used stool tests, at a specificity of 80-82%. The test was well received, with 99.5% of patients in a participation trial agreeing to testing, and of these, when the test was positive, 67% scheduled colonoscopy. Finally, 59% of patients who had a colonoscopy in this study had a finding requiring polypectomy or biopsy. Based on these data, the test was approved as a screening test in the US, for patients who are otherwise unscreened, a key advance for molecular diagnostics applications in the field of clinical epigenetics.
Highlights
Methylated Biomarkers in Cell Free Plasma DNAThe development of blood tests based on analysis of cell free nucleic acids, or so called ‘liquid biopsies’ in the past 10 years represents the confluence of advances in different fields of research through the 1980’s and 1990’s
Based on the clinical performance evaluation, the comparison with stool based FIT testing, and the observed degree of screening participation in the ADMIT trial, Epi proColon was approved by the US FDA as the first DNA methylation based test using cell free DNA in plasma as the analyte
This DNA promoter methylation test, which has similar sensitivity to the stool based FIT test, addresses the clinical challenge of reaching patients who are unwilling or unable to be screened for colorectal cancer by other recommended methods
Summary
Epigenetics research encompasses a growing number of mechanisms for gene regulation mediated through an expanding list of modifications of DNA, RNA and proteins [1]. It should not be surprising that dysfunction of these regulatory mechanisms, potentially as a consequence of aberrant modifications, can play a significant role in disease and cancer. As methylation levels were associated with transcription status, hypermethylation of such CpG islands was reported in the transition to cell immortalization [12] These observations of global hypomethylation and localized hypermethylation have led to multiple rationales for a role for aberrant DNA methylation in cancer. Pertinent to this review, altered DNA methylation patterns are one of the hallmarks of oncogenic transformation, and provide a rich potential source of biomarkers to exploit for molecular diagnostics
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