Abstract
BackgroundColorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90% survival rate. Currently less than 45% of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC.Methodology/Principal FindingsUsing a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48%) and 7/102 controls (7%). In the test study 73/126 CRCs (58%) and 18/183 control samples (10%) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72% (90/125 CRCs detected) while maintaining 90% specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was ∼20%.Conclusions/SignificanceAnalysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.
Highlights
Colorectal cancer (CRC) is one of the most common neoplasms found in men and women in the United States
In an initial study we presented the first level of evidence that Septin 9 (SEPT9), a DNA methylation-based biomarker, effectively discriminates CRC from normal specimens [21]
Moving forward in the process proposed by Pepe et al, in this report we provide the second level of evidence by presenting results from validation of clinical assay for SEPT9 in two large independent plasma sets demonstrating the potential of this marker for early detection of CRC
Summary
Colorectal cancer (CRC) is one of the most common neoplasms found in men and women in the United States. Improvements in feces-based tests by making them more sensitive and more user friendly have not increased compliance in CRC screening. Invasive screening tests such as colonoscopy or DNA methylation-based marker candidates for detection of CRC [15,16,17,18,19]. Translating such marker candidates into clinically validated and commercially viable tests has been exceedingly slow and inadequate.
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