Abstract
Methylated SEPT9 showed relatively low sensitivity in detecting early stage colorectal cancer (CRC) and advanced adenomas (AA) in plasma. Combination of multiple biomarkers was an effective strategy to improve sensitivity in early stage cancer diagnosis and screening. A new qPCR‐based assay combining the detection of methylated SEPT9 and SDC2 (ColoDefense test) was used. Methylation statuses of SEPT9 and SDC2 were examined in 40 sets of cancer tissues and paired adjacent tissues, 10 adenomatous polyps and 3 hyperplastic polyps (HP). Then evaluated with 384 plasma samples, including 117 CRC patients, 23 AA patients, 78 small polyps patients, and 166 normal individuals. The limit of detection of ColoDefense was about 25 pg per reaction. Both SEPT9 and SDC2 were shown by ColoDefense to be heavily methylated in CRC tissues when compared to paired paracancerous tissues and HP (P < .01). The sensitivities for detecting AA and stage I CRC by plasma SEPT9 methylation alone were 12.1% and 65.0%, and those by plasma SDC2 methylation alone were 43.5% and 55.0%. In comparison, the sensitivities to detect AA and stage I CRC by ColoDefense improved to 47.8% and 80.0%. The overall sensitivity of ColoDefense in detecting CRC was 88.9% (95% CI: 81.4%‐93.7%) with a specificity of 92.8% (95% CI: 87.4%‐96.0%). Detection of the combinatorial biomarker of methylated SEPT9 and/or SDC2 is a powerful, convenient and highly effective strategy for early CRC screening with high sensitivity and specificity.
Highlights
Colorectal cancer (CRC) is the most common malignancy of gastrointestinal tract and among the three most common cancer types worldwide.[1]
We evaluated the performance of a new blood‐ based early CRC screening assay, ColoDefense test, which combined the detection of SEPT9 and SDC2 methylation in a single qPCR reaction to improve the detection rate for early stage CRC and AA
It is a combinatorial assay that can detect two methylation biomarkers, SEPT9 and SDC2, simultaneously in a single qPCR reaction. Both SEPT9 and SDC2 genes were shown by ColoDefense test to be heavily methylated in CRC tissues when compared to paired paracancerous tissues and hyperplastic polyps (HP) tissues (P < .01)
Summary
Colorectal cancer (CRC) is the most common malignancy of gastrointestinal tract and among the three most common cancer types worldwide.[1]. It has been shown to have multiple alternatively spliced transcripts encoding at least 5 characterized polypeptides designated v1‐v5, some of which have been associated with ovarian, breast, and other cancers.[11] The promoter region of the V2 transcript of the SEPT9 gene has been shown to be hypermethylated and such hypermethylation is specific to CRC carcinogenesis.[12] methylated SEPT9 became the only blood‐based biomarker approved by FDA for CRC screening, and it has been used clinically for several years.[13,14] the sensitivity of SEPT9 methylation for CRC detection was relatively low, especially for early stage cancers and advanced adenomas (AA).[4,5] The syndecan‐2 protein encoded by SDC2 gene functions as an integral membrane protein and is known to participate in cell proliferation, cell migration, and cell‐matrix interactions via its receptor for extracellular matrix proteins.[15] Hypermethylation of SDC2 has been reported in malignant glioma,[16] recently, and it was found to be hypermethylated in the feces or blood samples of most CRC patients.[15,17] SDC2 methylation showed a higher sensitivity in detecting AA than SEPT9 methylation.[13]. We evaluated the performance of a new blood‐ based early CRC screening assay, ColoDefense test, which combined the detection of SEPT9 and SDC2 methylation in a single qPCR reaction to improve the detection rate for early stage CRC and AA
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