Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer
© Warren et al; licensee BioMed Central Ltd. 2011
Received: 13 September 2011
Accepted: 14 December 2011
Published: 14 December 2011
About half of Americans 50 to 75 years old do not follow recommended colorectal cancer (CRC) screening guidelines, leaving 40 million individuals unscreened. A simple blood test would increase screening compliance, promoting early detection and better patient outcomes. The objective of this study is to demonstrate the performance of an improved sensitivity blood-based Septin 9 (SEPT9) methylated DNA test for colorectal cancer. Study variables include clinical stage, tumor location and histologic grade.
Plasma samples were collected from 50 untreated CRC patients at 3 institutions; 94 control samples were collected at 4 US institutions; samples were collected from 300 colonoscopy patients at 1 US clinic prior to endoscopy. SEPT9 methylated DNA concentration was tested in analytical specimens, plasma of known CRC cases, healthy control subjects, and plasma collected from colonoscopy patients.
The improved SEPT9 methylated DNA test was more sensitive than previously described methods; the test had an overall sensitivity for CRC of 90% (95% CI, 77.4% to 96.3%) and specificity of 88% (95% CI, 79.6% to 93.7%), detecting CRC in patients of all stages. For early stage cancer (I and II) the test was 87% (95% CI, 71.1% to 95.1%) sensitive. The test identified CRC from all regions, including proximal colon (for example, the cecum) and had a 12% false-positive rate. In a small prospective study, the SEPT9 test detected 12% of adenomas with a false-positive rate of 3%.
A sensitive blood-based CRC screening test using the SEPT9 biomarker specifically detects a majority of CRCs of all stages and colorectal locations. The test could be offered to individuals of average risk for CRC who are unwilling or unable to undergo colonscopy.
It has been postulated that a screening test for colorectal cancer (CRC) performed on blood that is collected in the physician's office would encourage more patients to undergo screening, and could significantly decrease CRC mortality. Increased screening would also likely result in cost savings to the healthcare system, since more CRCs would be detected at an earlier stage and newer, more expensive chemotherapies could be avoided . In 2008, Lofton-Day et al.  described three blood-based molecular biomarkers for CRC that are shed from solid tumors into the bloodstream [3–5]. The same group further developed an assay to detect one of the candidates, Septin 9 (SEPT9), which was differentially methylated in CRC tissues  and can be sensitively and specifically detected in blood plasma [7, 8]. SEPT9 DNA methylation was analyzed in several case-control studies, involving more than 3,000 subjects, which demonstrated an overall CRC detection rate of 60 to 70% [7–9]. In 2010, the PRESEPT prospective screening study of the SEPT9 biomarker was completed, and the results were presented at the 2010 Digestive Disease Week (DDW) conference . Nearly 8,000 asymptomatic patients from 32 clinical sites in the United States and Germany undergoing routine screening colonoscopy participated in the study . Blood was collected for each subject, and the results of the SEPT9 test were compared to colonoscopy with regard to CRC detection . The SEPT9 test detected 67% of CRCs and had a false-positive rate of 11% , similar to results obtained in the previous case-control studies.
In this report, we describe an improved SEPT9 blood-based CRC screening test with a significant increase in sensitivity. Employing recent improvements for duplexing, amplifying and detecting SEPT9 methylated DNA, we demonstrate that the new test has dramatically improved performance when compared to the PRESEPT study method. In a case-control study, the new SEPT9 test is demonstrated to specifically identify CRCs from blood plasma with sensitivity similar to colonoscopy, exceeding the rates published for stool-based tests and previously described SEPT9 blood tests. The ability of the test to detect cancers originating from all large intestine locations is presented.
Human Plasma Samples
The clinical performance of the SEPT9 methylated DNA assay was measured using blinded plasma specimens collected from CRC patients and colonoscopy-verified control subjects. Specimens were collected from 50 untreated CRC patients prior to surgery at one US and two Russian institutions between July 2008 and March 2009. The average age of the cancer patients was 62 (range: 42 to 85) years. Control specimens were collected from 94 CRC-free subjects at four institutions in the US within one year of having a negative colonoscopy; collections occurred between July 2008 and June 2010. Control subjects had an average age of 58 (range: 40 to 86) years. A separate set of controls involving 98 younger subjects between the ages of 18 to 49 was collected at ARUP Laboratories between January and April 2011. The average age in this group was 32.
For the small prospective study, blood specimens were collected from 306 patients undergoing colonoscopy at a single community clinic in the US from March to June 2011; 300 of the subjects were evaluable. The average age of the cohort was 56 (range: 22 to 84) years; 195 of these were 50 to 75 (average 59) years of age, were asymptomatic, and underwent a routine screening colonoscopy.
Written informed consent was obtained from all study participants, adhering to local ethics guidelines.
Analytical performance of the blood-based SEPT9assay
Analytical performance of the assay was determined using CpGenome wholly methylated human genomic DNA (Chemicon/Millipore, Billerica, Massachusetts) added to pooled normal human plasma (Innovative Research, Novi, Michigan). The limit of detection of SEPT9 methylated DNA at the specimen level was 6.25 pg/ml (at least one out of the three reactions had SEPT9 detected 100% of the time). The limit of detection at the PCR replicate level was 50 pg/ml (all three out of three reactions had SEPT9 detected 100% of the time). For the comparison study with the PRESEPT Epi proColon PCR method, concentrations ranging from 6.25 to 100 pg/ml of wholly methylated human genomic DNA were used. DNA was extracted from multiple aliquots of each concentration, treated with bisulfite, and purified. Resultant DNA samples from each concentration were pooled, so that the same DNA substrate was used in the PCR method comparisons.
DNA Preparation and Bisulfite Conversion from Plasma Specimens
For each subject, 10 ml of blood was collected in an EDTA (ethylenediaminetetraacetic acid) vacutainer tube. Each tube was centrifuged for 12 minutes at 1350 × g ± 150 × g at room temperature. Plasma was transferred without disturbing the buffy coat to a clean 15 ml conical tube. The sample was centrifuged a second time for 12 minutes at 1350 × g ± 150 × g. Plasma was transferred without disturbing the pellet to a 4 ml tube and stored at -70°C. Total genomic DNA was extracted from 4 ml of plasma using a nucleic acid extraction kit from Chemagen (Chemagic NA Extraction kit catalog number 1045 distributed by PerkinElmer, Waltham, Massachusetts) following the product insert protocol. Sample DNA was treated with bisulfite conversion reagents prepared according to the protocol from deVos et al. . All bisulfite reagents were purchased from Sigma-Aldrich (St. Louis, Missouri). After bisulfite conversion, samples were purified using a bisulfite purification kit from Chemagen (Chemagic Bisulfite Purification Kit number 1036) following the product insert protocol. DNA was eluted in 55 μL of elution buffer. If not used immediately, eluted DNA was stored at -20°C for up to one week.
PCR amplification was performed in triplicate for each sample using a modified version of the protocol from deVos et al. . Septin 9 (SEPT9) and beta-actin (ACTB) control reactions were performed in the same reaction. All primers and probes were synthesized by Integrated DNA Technologies (Coralville, Iowa). Qiagen (Germantown, Maryland) 2X QuantiTect Multiplex Kit No ROX was used. The total volume of the PCR was 25 μL using 10 μL DNA and 12.5 μL 2X QuantiTect Kit. Sequences and final concentrations were as follows: SEPT9-FWD AAATAATCCCATCCAACTA (1.5 μM), SEPT9-REV GATT-dSp-GTTGTTTATTAGTTATTATGT (1.5 μM), SEPT9-Blocker GTTATTATGTTGGATTTTGTGGTTAATGTGTAG-SpC3 (1.0 μM), SEPT9-Probe FAM-TTAACCGCGAAATCCGAC-BHQ_1 (0.075 μM), ACTB-FWD GTGATGGAGGAGGTTTAGTAAGTT (0.2 μM), ACTB-REV CCAATAAAACCTACTCCTCCCTTAA (0.2 μM), ACTB-probe TEX615-ACCACCACCCAACACACAATAACAAACACA-IAbRQSp (0.075 μM). Real-time PCR was performed on the LC480 thermal cycler (Roche Applied Science, Indianapolis, Indiana) using the following cycling conditions: activation at 95°C for 30 minutes, 50 cycles of 95°C for 10 seconds, 56°C for 30 seconds, and final cooling to 40°C for 30 seconds. Heating rates were 4.4°C/second and cooling rates, 2.2°C/second. Data were acquired at the end of each 56°C step. Samples were analyzed using the AbsQuant/2ndDerivativeMax function of the LC480 software. For the comparison study, the PCR method was performed as described in the Epi proColon Instructions For Use pamphlet (Epigenomics AG, Berlin, Germany). Analysis was done using the AbsQuant/Fit points function of the LC480 software following the Epi proColon real-time PCR protocol.
PCR Data Analysis
In order to maximize sensitivity, SEPT9 was called positive if at least one of the triplicate reactions had detectable SEPT9. For plasma specimens that contain very low levels of DNA, SEPT9 was 'detected' if the quantification cycle ('crossing point', CP) was less than 45 cycles, the highest value reliably measured by the LC480 AbsQuant/2ndDerivativeMax analysis function. Plasma specimens were 'not detected' if the SEPT9 CP was not measurable or was ≥ 45.0 cycles and the ACTB CP was ≥ 36.0 cycles. If ACTB was not detected, eluted DNA specimens were diluted 1:10 in water and re-run; for these studies, a CP of 39.0 cycles for ACTB was the maximum value accepted in order to confirm a SEPT9 negative result.
For these NPV and PPV calculations, the prevalence of CRC in the screening population was assumed to be 1 in 200 based on the work of Lieberman .
Analytical performance of the improved blood-based SEPT9test
Clinical performance of the blood-based SEPT9test
SEPT9 detection in specimens collected prospectively from colonoscopy patients
(age 24-86 years)
(age 50-75 years)
Other cancer (carcinoid tumor)
Adenoma ≤ 10 mm
Adenoma > 10 mm
Other colonic findings
In several clinical studies, which together include over 10,000 subjects, SEPT9 has consistently demonstrated utility for detecting CRC in the blood, with previous publications citing a rate of 60% to 70% [2, 7, 8, 10]. In the PRESEPT prospective study of nearly 8,000 asymptomatic individuals undergoing routine CRC screening, the CRC detection rate was 67% with a specificity of 89%, similar to results obtained in case-control studies . Our publication describes an improved SEPT9 blood test with enhanced sensitivity, proven by direct comparison with the PRESEPT method using identical analytical specimens. In a case-control study of 144 blinded specimens, the improved SEPT9 blood test detected cancers of all stages and colorectal locations, including 87% of early stage cases (stages I and II). The new test exhibited an overall CRC detection rate of 90% at 88% specificity, contrasting historical studies of SEPT9.
Summary statistics for the SEPT9 test in colorectal cancer detection
Moderate Sensitivity, Moderate Specificity
Positive PCR replicates
1 out of 3
2 out of 3
3 out of 3
Positive predictive value
Negative predictive value
Although tissue studies showed that adenomas have elevated levels of methylated SEPT9 DNA comparable to CRCs (data not shown), the adenoma detection rate in the plasma was a modest 10% to 12%, consistent with previous studies of the SEPT9 biomarker [7, 10] and similar to that reported for a standard guaiac fecal occult blood test (FOBT) . Note that these early FOBT tests, which have been reported to detect lower percentages of colorectal cancers , were shown in several large prospective screening studies to provide a survival benefit to those who underwent screening when compared to those who did not [14–17]. There did not appear to be any specific types or size of adenomas that were more amenable to SEPT9 detection, although a more extensive study with larger numbers of specimens will be required. These results suggest that while the new method is very useful for detecting a majority of CRCs of all stages and locations from the plasma, a blood-based test for SEPT9 alone will not be sufficient to detect mucosal precancerous lesions.
Methylated SEPT9 may normally play a role in embryonic development in humans. In evaluating SEPT9 methylation in normal healthy young control subjects under the age of 50 years, four women demonstrated high concentrations of methylated SEPT9 DNA (Warren et al., unpublished data). These women were subsequently found to be pregnant. Additional studies with 20 pregnant women showed that 100% of these subjects had very high concentrations of methylated SEPT9 in their plasma. Like other well-known cancer biomarkers such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and CA-125, SEPT9 is implicated in both embryogenesis and oncogenesis. Future studies are planned to determine whether the sensitive SEPT9 blood test might be useful for therapeutic monitoring and early detection of relapse, such as CEA and CA-125.
Although it is clear that CRC screening reduces mortality by detecting the disease in its earliest stages when it is most effectively treated [14–28], only one half of Americans age 50 and older currently undergo any kind of screening [29, 30]. Patient compliance appears to be a major hurdle . Even those individuals who otherwise adhere to screening recommendations for other cancers, such as those who routinely undergo mammography, do not faithfully follow colorectal screening guidelines . Physician recommendation plays a significant role in whether individuals are screened , however patient preference appears to strongly determine what method, if any, is ultimately used . Reasons for not complying with colonoscopy referral include the time-consuming nature of the procedure and concern about invasiveness . Alternative methods for CRC screening such as fecal testing have declined in recent years . In addition to the challenges of patient compliance with stool testing, such as the requirement for multiple samples and the handling of specimens, the performance of these tests is quite variable, with cancer detection rates ranging from 30% to 85% (13). Newer stool based tests such as the immunochemical FOBT (FIT), have demonstrated sensitivity for adenoma detection . While the SEPT9 methylated DNA test may perform comparably to colonoscopy in detecting CRCs, it lacks the advantage of being potentially curative, and does not perform well for adenoma detection. Nonetheless, we believe that a blood-based CRC test, whereby specimens are collected in the primary care setting every two or three years, will attract a significant fraction of those individuals who are otherwise non-compliant with recommended screening guidelines. Studies are underway to gain a better understanding as to whether a blood-based test will encourage individuals in the average risk screening population to undergo testing of this type.
- ACTB :
carbohydrate antigen 125
Digestive Disease Week
fecal immunochemical test
fecal occult test
gastrointestinal: pg: picogram
negative predictive value
polymerase chain reaction
positive predictive value
- SEPT9 :
septin 9 gene
We would like to thank all of the study participants for agreeing to participate in medical research. We also thank Dan Anderson for his insights into the clinical implementation of the test, Melinda Jones, Kyle Rasmussen and the staff of the University of Utah Redwood Health Center Endoscopy Clinic for help with study participant recruitment and specimen collection. Thank you to Maria Erali for her original artistic contribution to Figure 3 and Andy Wilson for statistical discussions. Finally, we are grateful to Noriko Kusukawa, Carl Wittwer and Bill Hokanson for critically reviewing this manuscript, and for many helpful discussions.
This work was entirely funded by ARUP Laboratories, Inc., a not-for-profit, wholly-owned enterprise of the University of Utah
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