The Study On The Application Value Of Serum Methylated SEPT9 For Optimizing Screening Scheme Of Colorectal Cancer

【Background】Colorectal cancer(colorectal cancer, CRC) is the most common gastrointestinal cancer worldwide, and there are around 694,000 deaths caused by colorectal cancer. The main reason for the high mortality rate is most of the CRC patients were diagnosed at the advanced stage and had no chance for curative therapies. Early colorectal cancer screening is an effective measure which can improve the proportion of early CRC detection, and consequently improve the prognosis and reduce the mortality of CRC. Currently, colorectal cancer screening methods including fecal occult blood test(Fecal occult blood testing, FOBT) and colonoscopy(colonoscopy, CSPY). However, the disadvantages of these tests, such as low specificity, inconvenience of getting the samples, and invasive procedures, limited the its extensive usage in clinical practice. Therefore, the development of efficient and simple screening programs is still important for the improvement of CRC patient outcome..Asia-Pacific Colorectal Screening Score(Asia-Pacific Colorectal Screening Score, APCS), which is determined by age, gender, smoking, and diagnosis of CRC in any first-degree relatives, is verified by several prospective multi-center large clinical studies,. The APCS high-risk group had about four times higher risk of CRC than the low-riskAPCS group. APCS score is considered as one of the most simple and effective screening methods for CRC and is widely used in Asia-Pacific countries. However, the low-risk CRC people identified by APCS score have to underwent FOBT test before the screening colonoscopy. Only those with high-risk of CRC by FOBT test should accept screening colonoscopy. So the limitations of FOBT would be the obstruction of the application of APCS application.The test of tumor biomarkers is a common noninvasive screening method. Several studies showed that mathylated SEPT9 DNA(mathylated SEPT9 DNA, m SEPT9) in plasma is a specific marker of CRC. And, the concentration of m SEPT9 in plasma correlated with clinical stages of CRC very well. Several studies demonstrated that the addition of m SEPT9 test to the APCS score could improve the specificity. And, m SEPT9 was validated as a better markers of CRC than FOBT in previous studies. However, the study of comparing the effectivity of serum m SEPT9 with current screening schemes is rarely reported.【Objectiv】The purposes of the present study were to evaluate the sensitivity and specificity of m SEPT9 test for early screening of CRC, and to evaluate the usefulness of blood m SEPT9 test in the optimization of APCS screening scheme.【Methods】1. Blood samples of asymptomatic CRC patients and health control people were collected, and the plasm m SEPT9 levels were tested. Thereafter, univariate and multivariate logistic regression were performed to evaluate whether m SEPT9 is an independent risk factors for CRC.2. The clinical and pathological data were collected. And then, the correlation between the m SEPT9 and the clinical and pathological characteristics were evaluated.3. The usefulness of m SEPT9 for the CRC screening for APCS low-risk patients were evaluated. At last, the new screening system will be compared with the previous screening system in sensitivity and specificity.【Results】1. The sensitivity, specificity, positive predictive value, and negative predictive value of the plasma m SEPT9 for Colorectal Adenomatous Polyps were 26.03%, 81.22%, 33.93%, and 74.77%, respectively. The specificity and positive predictive value of m SEPT9 were higher than FOBT(specificity: 64.97%, positive predictive value: 31.11%) and BMI(specificity: 50.69%, positive predictive value: 32.08%).2. The positive plasma mSEPT9 proportions were 71.05(54/76), 5.80%(4/69), and 3.68%(5/136)in the CRC group, Colorectal Adenomatous Polyps group, and health control group. The positive plasma m SEPT9 proportion of the CRC group was significantly higher than the other groups(χ2=141.7,P<0.01). And, plasma m SEPT9 had significantly higher sensitivity(71.05%( 54/76)) and specificity(95.61%(196/205)) than CEA, CA19-9, and the combination of CEA and CA19-9(χ2=20.689, 42.577, and 14.119,P<0.01 in all of the tests). The plasma m SEPT9 concentrations correlated well to the tumor size, histological stage, and clinical stage, and did not correlate to the age, gender, tumor position, differentiation degree, and lymphatic metastasis.3. In the APCS low-risk group, m SEPT9, FOBT, and BMI were not significantly different in the efficacy of CRC diagnosis(χ2=0.944,P>0.05). However, the specificity and positive predictive value of m SEPT9(85.71% and 33.33%) were higher than FOBT(66.33% and 29.79%) and BMI(41.84% and 24.00%).4. In the APCS low-risk group, the combination of FOBT and m SEPT9, the combination of FOBT and BMI, and the combination of m SEPT9 and BMI were not significantly different in the efficacy of CRC diagnosis(χ2=0.490,P>0.05). However, the specificity and positive predictive value of the combination of FOBT and m SEPT9(93.33% and 42.85%) were higher than the combination of FOBT and BMI(58.33% and 31.03%) and the combination of m SEPT9 and BMI(81.39% and 27.27%).【Conclusions】1. Plasma m SEPT9 test had high specificity and positive predictive value for the diagnosis of CRC and most likely could be used for the early screening of CRC.2. In Chinese, Plasma m SEPT9 were verified as one of the useful biomarkers in plasma, and most likely could be used for the early screening of CRC in Chinese people.3. Plasma m SEPT9 and the combination of m SEPT9 and FOBT could improve the efficacy of APCS screening system. Plasma m SEPT9 test most likely could be useful for optimize the early CRC screening scheme.