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BACKGROUND: This study was designed to compare the diagnostic efficacy of mSEPT9 to four blood markers (CEA, CA19-9, platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)). In addition, we aimed to determine the combined diagnostic efficacy of mSEPT9, CEA, CA19-9, PLR and NLR in colorectal cancer. METHODS: A total of 567 participants were enrolled in the study, including 308 CRC patients, 61 colorectal polyp patients and 198 healthy subjects confirmed by colonoscopy and/or tissue biopsy. Plasma samples were collected for tests. RESULTS: The positive rate of mSEPT9 in CRC (71.8%) was markedly higher than that in either the colorectal polyps group (27.9%) or the healthy controls (6.1%) (P < 0.001). The levels of CEA, CA19-9, NLR and PLR in the CRC group were significantly higher than those in the non-CRC groups (P < 0.05). ROC curves comparison analyses showed that the diagnostic efficacy of mSEPT9 alone in CRC was significantly higher than CEA, CA19-9, NLR and PLR alone. The combination of mSEPT9 with CEA, CA19-9 and PLR showed superior diagnostic value. In addition, binary logistic regression was also used to build a better model for clinical diagnosis of CRC. On univariable analyses, age, mSEPT9, CEA, CA 19-9, PLR and NLR were independent predictors of CRC. When these covariates were fitted in multivariable models, the ones with positive detection of mSEPT9, CEA, CA 19-9 and PLR were more likely to have CRC. CONCLUSIONS: This research revealed a significant association between mSEPT9 status and the clinicopathological characteristics of CRC patients, and the combination of mSEPT9, CEA, CA19-9 and PLR could significantly improve diagnostic efficacy in CRC.

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BACKGROUND: The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. METHODS: We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. RESULTS: The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400 ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. CONCLUSIONS: m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs.

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BACKGROUND: Hepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. OBJECTIVE: Our study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. METHODS: This is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at -80 °C until the end of recruitment. Gas chromatography-mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis-mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. RESULTS: The recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. CONCLUSIONS: There is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44264.

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BACKGROUND AND AIMS: Methylated Septin9 (mSEPT9) has been suggested for CRC detection. To assess the performance of mSEPT9 in Western China, we compared its diagnostic and recurrence monitoring values with fecal occult blood test (FOBT), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). MATERIAL AND METHODS: Overall 300 subjects including 209 CRC patients and 91 healthy subjects, who have performed mSEPT9, FOBT, CEA and CA19-9 tests, were involved. Sensitivity, specificity, and area under the ROC curve (AUC) were used to evaluate the efficacy of each method. RESULTS: Plasma mSEPT9 demonstrated an AUC of 0.860, and a sensitivity of 76.4 % for CRC detection. The sensitivity of mSEPT9 was higher than FOBT, CEA and CA 19-9. Though mSEPT9 presented a larger or equal sensitivity for stage Ⅱ-IV CRCs, FOBT showed a better sensitivity for stage I CRCs. Logistical analysis showed the ones with positive mSEPT9, FOBT and CEA were more likely to have CRC (all P < 0.01). Then, the three biomarkers built the nomogram predicting the probability of having CRC. The sensitivity of mSEPT9 was also much higher than CEA for CRC recurrence monitoring. CONCLUSION: The mSEPT9 test performed better than traditional tests for CRC detection, and should be recommended for FOBT-positive ones or individuals who refuse FOBT.

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Early-onset colorectal cancer (EOCRC), defined as a diagnosis under age 50, is an emerging public health burden. As many of these individuals fall outside of screening guidelines, the development of a minimally invasive, accurate screening modality for this population is warranted. We evaluated the FDA-approved blood-based biomarker methylated Septin9 (mSEPT9) test as screening tool for EOCRC. EOCRC plasma, healthy plasma, and serum-free conditioned media from cancer cell lines was collected. Cell-free DNA (cfDNA) was isolated and bisulfite converted for use in the assay. mSEPT9 and ACTB measured using Epi proColon® V2.0. EOCRC plasma was collected at Massachusetts General Hospital (2005-2019) and controls were collected at the National Institutes of Health and by ZenBio Inc. (prior to 2019). Twenty-seven EOCRC cases, 48 healthy controls <50 years old, and 39 healthy controls ≥50 years old were included in this study. mSEPT9 was detected more frequently in EOCRC cases (88.9%) compared to healthy controls age <50 (4.2%) and ≥50 (15.4%), respectively (p<0.001). The sensitivity, specificity, positive predictive value, and negative predictive values of the mSEPT9 assay to detect EOCRC was 90.8% (95% CI: 84.7-96.9%), 88.9% (95% CI: 77.0-100.0%), 96.3% (95% CI: 92.3-100.0%), and 75.0% (95% CI 60.0-90.0%), respectively, compared to all healthy controls. mSEPT9 cfDNA level was an independent predictor of survival (p=0.02). mSEPT9 is a sensitive and specific biomarker for EOCRC detection. These results suggest that mSEPT9 may be useful in the detection of EOCRC, providing a minimally invasive method for screening in this growing population of CRC patients.

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The study aims to examine the risk factors for increased colorectal cancer (CRC) markers in patients with type 2 diabetes mellitus (T2DM). The 229 patients retrospectively reviewed were categorized into two groups: CRC tumor marker-positive and -negative groups. Patients who tested positive for all three of the following CRC markers were included in the CRC tumor marker-positive group: serum carcinoembryonic antigen, carbohydrate antigen 19-9 and septin9 methylation. Univariate analysis revealed that most CRC marker-positive patients had higher age, a family history of CRC, history of smoking and alcohol intake, high body mass index (BMI; overweight), longer history of T2DM, worse diabetes control (with high glycated hemoglobin A1c [HbA1c]), lower level of serum vitamin D (VD), high-density lipoprotein cholesterol and higher level of total cholesterol and triglyceride (TG). Logistic regression analysis showed that BMI, VD, HbA1c and TG were independent predictors of CRC marker-positive status (OR, 95% confidence intervals and P values were 1.912 [1.346-2.716], <0.001; 0.773 [0.633-0.943], 0.011; 9.082 [3.52-23.433], <0.001; and 11.597 [3.267-41.164], <0.001, respectively). In this retrospective study, high BMI, HbA1c and TG as well as low level of VD were correlated with CRC tumor marker-positive status in T2DM patients. Patients with these risk factors may benefit from more frequent screening for CRC tumor markers.

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BACKGROUND: The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. AIM: To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. METHODS: A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. RESULTS: In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. CONCLUSION: MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.

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BACKGROUND: Colorectal cancer (CRC) is a common and lethal disease in the world. There is an increasing number of cases in Taiwan and a higher rate at advanced stages. The immune fecal occult blood test (iFOBT) has been used as a screening method in Taiwan for years. A new novel diagnostic tool, the Methylated Septin-9 (MS-9) DNA blood test, had been reported to have high sensitivity and specificity for CRC detection. There are no available data in Taiwan, so we conducted this prospective randomized trial to investigate the relationship among the MS-9 DNA blood test, iFOBT, and a combination of the two tests for diagnosing CRC in Taiwanese people. METHODS: From July 1, 2012 to December 31, 2013, we prospectively selected 60 plasma samples from patients who were diagnosed with CRC and otherwise, the healthy group by colonoscopy in our hospital. Patients were divided into the CRC group and healthy group. CRC stages 0, I, II and stages III and IV were separately analyzed. We calculated the sensitivity and specificity of each group to determine the relationship among the MS-9 DNA blood test, iFOBT, and a combination of the two tests for diagnosing CRC in Taiwanese people. RESULTS: The results of the MS-9 DNA blood test for the 60 samples were divided into three groups, and the sensitivity as well as the specificity of the MS-9 DNA blood test to detect CRC were 47% and 89%, respectively. The results of iFOBT were also divided into three groups, and had higher sensitivity (84%) but lower specificity (55%) using iFOBT to detect CRC. Higher rates could be predicted to detect CRC if both the tests were positive. CONCLUSIONS: A combined MS-9 DNA blood test and iFOBT may help in a higher detection rate of CRC. It could be offered to individuals who are unwilling or unable to undergo colonoscopy. Further large prospective, randomized studies are needed in the future.

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