KCNQ5 and C9orf50 Methylation in Stool DNA for Early Detection of Colorectal Cancer

BackgroundAberrant DNA methylation has emerged as a class of promising biomarkers for early colorectal cancer (CRC) detection, but the performance of methylated C9orf50 and methylated KCNQ5 in stool DNA has never been evaluated.MethodsMethylation specific quantitative PCR (qPCR) assays for methylated C9orf50 and methylated KCNQ5 were developed. The methylation levels of C9orf50 and KCNQ5 in 198 CRC patients, 20 advanced adenoma (AA) patients, 101 small polyp (SP) patients, and 141 no evidence of disease (NED) subjects were analyzed.ResultsThe methylation levels of both KCNQ5 and C9orf50 genes were significantly higher in CRC and AA groups than those in SP and NED groups, but showed no significant difference among different stages of CRC. The sensitivities of methylated KCNQ5 and methylated C9orf50 for CRC detection were 77.3% (95% CI: 70.7–82.8%) and 85.9% (95% CI: 80.0–90.2%) with specificities of 91.5% (95% CI: 85.3–95.3%) and 95.0% (95% CI: 89.7–97.8%), respectively. When C9orf50 and methylated KCNQ5 were combined, the clinical performance for CRC detection was similar to that of methylated C9orf50 alone.ConclusionsStool DNA based methylated C9orf50 test has the potential to become an alternative approach for CRC screening and prevention.

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Combining Serum DNA Methylation Biomarkers and Protein Tumor Markers Improved Clinical Sensitivity for Early Detection of Colorectal Cancer

International Journal of Genomics ◽

10.1155/2021/6613987 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Guoying Zhang ◽

Fang He ◽

Guodong Zhao ◽

Zihui Huang ◽

Xiang Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Markers ◽

Clinical Performance ◽

Screening Method ◽

Blood Chemistry ◽

Advanced Adenoma ◽

Crc Screening ◽

Control Subjects ◽

Incidence And Mortality ◽

Small Polyp

Background. Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide and in China. Early CRC screening is the best approach to reduce its incidence and mortality rates. The ColoDefense test, a multiplex qPCR assay simultaneously detecting both methylated SEPT9 and SDC2 genes, has demonstrated improved clinical performance on either methylation biomarker alone for CRC screening with both blood and stool samples. Method. Leftover blood chemistry test samples from 125 CRC, 35 advanced adenoma, and 35 small polyp patients and 92 healthy control subjects were examined by the ColoDefense test. Among these samples, the levels of three circulating tumor markers, CEA, AFP, and CA19-9, were also measured for 106 CRC, 28 advanced adenoma, and 20 small polyp patients and all control subjects. Results. Due to the smaller volume and extended storage in nonfrozen state, the ColoDefense test with these samples exhibited reduced performance for all stages of CRC and advanced adenomas. The performance of CEA, AFP, and CA19-9 and their various combinations was also evaluated for CRC screening to identify the tumor marker combinations with the best performance. When combined with the ColoDefense test, the identified combinations did improve the clinical performance. Conclusion. These results suggested a rational path towards developing a CRC screening method that takes advantage of leftover blood chemistry test samples. The successful development of such a method will undoubtedly help promote early CRC screening by increasing its accessibility for the general public.

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Colorectal cancer screening using a stool DNA-based SDC2 methylation test: a multicenter, prospective trial

BMC Gastroenterology ◽

10.1186/s12876-021-01759-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chang Woo Kim ◽

Hyunjin Kim ◽

Hyoung Rae Kim ◽

Bong-Hyeon Kye ◽

Hyung Jin Kim ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Early Detection ◽

Prospective Trial ◽

Screening Colonoscopy ◽

Quantitative Detection ◽

Screening Programs ◽

Crc Screening ◽

Stool Dna ◽

Dna 2

Abstract Background Prevention and early detection of colorectal cancer (CRC) is a global priority, with many countries conducting population-based CRC screening programs. Although colonoscopy is the most accurate diagnostic method for early CRC detection, adherence remains low because of its invasiveness and the need for extensive bowel preparation. Non-invasive fecal occult blood tests or fecal immunochemical tests are available; however, their sensitivity is relatively low. Syndecan-2 (SDC2) is a stool-based DNA methylation marker used for early detection of CRC. Using the EarlyTect™-Colon Cancer test, the sensitivity and specificity of SDC2 methylation in stool DNA for detecting CRC were previously demonstrated to be greater than 90%. Therefore, a larger trial to validate its use for CRC screening in asymptomatic populations is now required. Methods All participants will collect their stool (at least 20 g) before undergoing screening colonoscopy. The samples will be sent to a central laboratory for analysis. Stool DNA will be isolated using a GT Stool DNA Extraction kit, according to the manufacturer’s protocol. Before performing the methylation test, stool DNA (2 µg per reaction) will be treated with bisulfite, according to manufacturer’s instructions. SDC2 and COL2A1 control reactions will be performed in a single tube. The SDC2 methylation test will be performed using an AB 7500 Fast Real-time PCR system. CT values will be calculated using the 7500 software accompanying the instrument. Results from the EarlyTect™-Colon Cancer test will be compared against those obtained from colonoscopy and any corresponding diagnostic histopathology from clinically significant biopsied or subsequently excised lesions. Based on these results, participants will be divided into three groups: CRC, polyp, and negative. The following clinical data will be recorded for the participants: sex, age, colonoscopy results, and clinical stage (for CRC cases). Discussion This trial investigates the clinical performance of a device that allows quantitative detection of a single DNA marker, SDC2 methylation, in human stool DNA in asymptomatic populations. The results of this trial are expected to be beneficial for CRC screening and may help make colonoscopy a selective procedure used only in populations with a high risk of CRC. Trial registration: This trial (NCT04304131) was registered at ClinicalTrials.gov on March 11, 2020 and is available at https://clinicaltrials.gov/ct2/show/NCT04304131?cond=NCT04304131&draw=2&rank=1.

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Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening in a large, nationally insured cohort

International Journal of Colorectal Disease ◽

10.1007/s00384-021-03956-0 ◽

2021 ◽

Author(s):

Lesley-Ann Miller-Wilson ◽

Lila J Finney Rutten ◽

Jack Van Thomme ◽

A Burak Ozbay ◽

Paul J Limburg

Keyword(s):

Colorectal Cancer ◽

National Sample ◽

Adherence Rate ◽

Average Risk ◽

Cross Sectional ◽

Commercial Insurance ◽

Dna Test ◽

Crc Screening ◽

Stool Dna ◽

Insured Patients

Abstract Purpose Colorectal cancer (CRC) is the second most deadly cancer in the USA. Early detection can improve CRC outcomes, but recent national screening rates (62%) remain below the 80% goal set by the National Colorectal Cancer Roundtable. Multiple options are endorsed for average-risk CRC screening, including the multi-target stool DNA (mt-sDNA) test. We evaluated cross-sectional mt-sDNA test completion in a population of commercially and Medicare-insured patients. Methods Participants included individuals ages 50 years and older with commercial insurance or Medicare, with a valid mt-sDNA test shipped by Exact Sciences Laboratories LLC between January 1, 2018, and December 31, 2018 (n = 1,420,460). In 2020, we analyzed cross-sectional adherence, as the percent of successfully completed tests within 365 days of shipment date. Results Overall cross-sectional adherence was 66.8%. Adherence was 72.1% in participants with Traditional Medicare, 69.1% in participants with Medicare Advantage, and 61.9% in participants with commercial insurance. Adherence increased with age: 60.8% for ages 50–64, 71.3% for ages 65–75, and 74.7% for ages 76 + years. Participants with mt-sDNA tests ordered by gastroenterologists had a higher adherence rate (78.3%) than those with orders by primary care clinicians (67.2%). Geographically, adherence rates were highest among highly rural patients (70.8%) and ordering providers in the Pacific region (71.4%). Conclusions Data from this large, national sample of insured patients demonstrate high cross-sectional adherence with the mt-sDNA test, supporting its role as an accepted, noninvasive option for average-risk CRC screening. Attributes of mt-sDNA screening, including home-based convenience and accompanying navigation support, likely contributed to high completion rates.

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Artificial intelligence assisted standard white light endoscopy accurately characters early colorectal cancer: a multicenter diagnostic study

10.1101/2020.02.21.20025650 ◽

2020 ◽

Author(s):

Sijun Meng ◽

Yueping Zheng ◽

Ruizhang Su ◽

Wangyue Wang ◽

Yu Zhang ◽

...

Keyword(s):

Artificial Intelligence ◽

Colorectal Cancer ◽

Malignant Potential ◽

Early Colorectal Cancer ◽

Diagnostic Study ◽

Internal Validation ◽

White Light Endoscopy ◽

Incidence And Mortality ◽

Validation Set ◽

Screening And Prevention

ABSTRACTColorectal cancer (CRC) is the third in incidence and mortality1 of cancer. Screening with colonoscopy has been shown to reduce mortality by 40-60%2. Challenge for screening indistinguishable precancerous and noninvasive lesion using conventional colonoscopy was still existing3. We propose to establish a propagable artificial intelligence assisted high malignant potential early CRC characterization system (ECRC-CAD). 4,390 endoscopic images of early CRC were used to establish the model. The diagnostic accuracy of high malignant potential early CRC was 0.963 (95% CI, 0.941-0.978) in the internal validation set and 0.835 (95% CI, 0.805-0.862) in external datasets. It achieved better performance than the expert endoscopists. Spreading of ECRC-CAD to regions with different medical levels can assist in CRC screening and prevention.

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Retrospective analysis of LNM risk factors and the effect of chemotherapy in early colorectal cancer: A Chinese multicenter study

BMC Cancer ◽

10.1186/s12885-020-07363-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Chunyan Zeng ◽

Dandan Xiong ◽

Fei Cheng ◽

Qingtian Luo ◽

Qiang Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Multicenter Study ◽

Tumor Size ◽

Lymphovascular Invasion ◽

Univariate Analysis ◽

Tumor Location ◽

Early Colorectal Cancer ◽

Depth Of Invasion ◽

Significant Difference

Abstract Background Estimating the risk of lymph node metastasis (LNM) is crucial for determining subsequent treatments following curative resection of early colorectal cancer (ECC). This multicenter study analyzed the risk factors of LNM and the effectiveness of postoperative chemotherapy in patients with ECC. Methods We retrospectively analyzed the data of 473 patients with ECC who underwent general surgery in five hospitals between January 2007 and October 2018. The correlations between LNM and sex, age, tumor size, tumor location, endoscopic morphology, pathology, depth of invasion and tumor budding (TB) were directly estimated based on postoperative pathological analysis. We also observed the overall survival (OS) and recurrence in ECC patients with and without LNM after matching according to baseline measures. Results In total, 473 ECC patients were observed, 288 patients were enrolled, and 17 patients had LNM (5.90%). The univariate analysis revealed that tumor size, pathology, and lymphovascular invasion were associated with LNM in ECC (P = 0.026, 0.000, and 0.000, respectively), and the multivariate logistic regression confirmed that tumor size, pathology, and lymphovascular invasion were risk factors for LNM (P = 0.021, 0.023, and 0.001, respectively). There were no significant differences in OS and recurrence between the ECC patients with and without LNM after matching based on baseline measures (P = 0.158 and 0.346, respectively), and no significant difference was observed between chemotherapy and no chemotherapy in ECC patients without LNM after surgery (P = 0.729 and 0.052). Conclusion Tumor size, pathology, and lymphovascular invasion are risk factors for predicting LNM in ECC patients. Adjuvant chemotherapy could improve OS and recurrence in patients with LNM but not always in ECC patients without LNM.

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Fecal DNA Testing for Colorectal Cancer Screening

Annual Review of Medicine ◽

10.1146/annurev-med-103018-123125 ◽

2020 ◽

Vol 71 (1) ◽

pp. 59-69 ◽

Cited By ~ 5

Author(s):

John M. Carethers

Keyword(s):

Colorectal Cancer ◽

Average Risk ◽

Fecal Dna ◽

Polyp Detection ◽

Serrated Polyps ◽

Crc Screening ◽

Epigenetic Biomarkers ◽

Life Years ◽

Screening Strategies ◽

Stool Dna

Fecal (or stool) DNA examination is a noninvasive strategy recommended by several medical professional societies for colorectal cancer (CRC) screening in average-risk individuals. Fecal DNA tests assay stool for human DNA shed principally from the colon. Colonic lesions such as adenomatous and serrated polyps and cancers exfoliate cells containing neoplastically altered DNA that may be detected by sensitive assays that target specific genetic and epigenetic biomarkers to discriminate neoplastic lesions from non-neoplastic tissue. Cross-sectional validation studies confirmed initial case-control studies’ assessment of performance of an optimized multitarget stool DNA (mt-sDNA) test, leading to approval by the US Food and Drug Administration in 2014. Compared to colonoscopy, mt-sDNA showed sensitivity of 92% for detection of CRC, much higher than the 74% sensitivity of another recommended noninvasive strategy, fecal immunochemical testing (FIT). Detections of advanced adenomas and sessile serrated polyps were higher with mt-sDNA than FIT (42% versus 24% and 42% versus 5%, respectively), but overall specificity for all lesions was lower (87% versus 95%). The mt-sDNA test increases patient life-years gained in CRC screening simulations, but its cost relative to other screening strategies needs to be reduced by 80–90% or its sensitivity for polyp detection enhanced to be cost effective. Noninvasive CRC screening strategies such as fecal DNA, however, have the potential to significantly increase national screening rates due to their noninvasive nature and convenience for patients.

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Multitarget stool DNA test: clinical performance and impact on yield and quality of colonoscopy for colorectal cancer screening

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2016.11.012 ◽

2017 ◽

Vol 85 (3) ◽

pp. 657-665.e1 ◽

Cited By ~ 19

Author(s):

David H. Johnson ◽

John B. Kisiel ◽

Kelli N. Burger ◽

Douglas W. Mahoney ◽

Mary E. Devens ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Screening ◽

Colorectal Cancer Screening ◽

Clinical Performance ◽

Dna Test ◽

Yield And Quality ◽

Stool Dna

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Tailored message interventions versus typical messages for increasing participation in colorectal cancer screening among a non-adherent population: A randomized controlled trial

BMC Public Health ◽

10.1186/s12889-016-3069-y ◽

2016 ◽

Vol 16 (1) ◽

Cited By ~ 10

Author(s):

Kei Hirai ◽

Yoshiki Ishikawa ◽

Jun Fukuyoshi ◽

Akio Yonekura ◽

Kazuhiro Harada ◽

...

Keyword(s):

Colorectal Cancer ◽

Randomized Controlled Trial ◽

Screening Program ◽

Controlled Trial ◽

Baseline Survey ◽

Attendance Rates ◽

Community Based ◽

Crc Screening ◽

Randomized Controlled ◽

Significant Difference

Abstract Background The purpose of this study was to examine the effectiveness and cost-efficiency of a tailored message intervention compared with a non-tailored message intervention for increasing colorectal cancer (CRC) screening rates among a non-adherent population, in a community-based client reminder program. Methods After a baseline survey for psychological segmentation, 2140 eligible individuals were randomly assigned either to a group with a tailored matched-message condition (N = 356), a group with a non-tailored unmatched-message condition (N = 355), or to two control groups, one using a typical message with a professional design (N = 717) and one without a professional design (N = 712). The main outcome measure was attendance rates in a community-organized CRC screening program within five months of receiving a print reminder. Results There was a significant difference in fecal occult blood test (FOBT) attendance rates at follow-up assessments between the tailored matched-message condition (14.0 %) and the control (9.9 %; OR = 1.48, p = 0.026), while there was no significant difference between the unmatched-message condition (11.0 %) and the control (OR = 1.12, p = 0.558), and between the matched-message condition and the unmatched-message condition (OR = 1.32, p = 0.219). The cost of a one-person increase in FOBT screening was 3,740 JPY for the tailored matched-message condition, while it was 2,747 JPY for the control. Conclusions A tailored-message intervention for segmented individuals designed to increase CRC screening rates in a community-based client reminder program was significantly effective compared to a usual reminder, but not more effective than an unmatched message in a randomized controlled trial, and was not sufficiently effective to highlight its value from a cost perspective. Therefore, the tailored intervention including target segmentation needs to be improved for future implementation in a CRC screening program for a non-adherent population. Trial registration UMIN Clinical Trials Registry UMIN000004384. Date of Registration: March 2011.

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Retrospective analysis for the LNM risk factors and effect of chemotherapy for the early colorectal cancer: A Chinese multicenter study

10.21203/rs.3.rs-25244/v5 ◽

2020 ◽

Author(s):

Chunyan Zeng ◽

Dandan Xiong ◽

Fei Cheng ◽

Qingtian Luo ◽

Qiang Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Multicenter Study ◽

Tumor Size ◽

Lymphovascular Invasion ◽

Univariate Analysis ◽

Tumor Location ◽

Early Colorectal Cancer ◽

Depth Of Invasion ◽

Significant Difference

Abstract Background Estimating the risk of lymph node metastasis (LNM) is crucial for determining subsequent treatments following curative resection of early colorectal cancer (ECC). This multicenter study analyzed the risk factors of LNM and the effectiveness of postoperative chemotherapy in patients with ECC.Methods We retrospectively analyzed the data of 473 patients with ECC who underwent general surgery in five hospitals between January 2007 and October 2018. The correlations between LNM and sex, age, tumor size, tumor location, endoscopic morphology, pathology, depth of invasion and tumor budding (TB) were directly estimated based on postoperative pathological analysis. We also observed the overall survival (OS) and recurrence in ECC patients with and without LNM after matching according to baseline measures. Results In total, 473 ECC patients were observed, 288 patients were enrolled, and 17 patients had LNM (5.90%). The univariate analysis revealed that tumor size, pathology, and lymphovascular invasion were associated with LNM in ECC (P=0.026, 0.000, and 0.000, respectively), and the multivariate logistic regression confirmed that tumor size, pathology, and lymphovascular invasion were risk factors for LNM (P=0.021, 0.023, and 0.001, respectively). There were no significant differences in OS and recurrence between the ECC patients with and without LNM after matching based on baseline measures (P=0.158 and 0.346, respectively), and no significant difference was observed between chemotherapy and no chemotherapy in ECC patients without LNM after surgery (P=0.729 and 0.052).Conclusion Tumor size, pathology, and lymphovascular invasion are risk factors for predicting LNM in ECC patients. Adjuvant chemotherapy could improve OS and recurrence in patients with LNM but not always in ECC patients without LNM.

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Quality Improvement of Sample Collection Increases the Diagnostic Accuracy of Quantitative Fecal Immunochemical Test in Colorectal Cancer Screening: A Pilot Study

Frontiers in Medicine ◽

10.3389/fmed.2021.762560 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ru-chen Zhou ◽

Pei-zhu Wang ◽

Yue-yue Li ◽

Yan Zhang ◽

Ming-jun Ma ◽

...

Keyword(s):

Colorectal Cancer ◽

Diagnostic Accuracy ◽

Fecal Immunochemical Test ◽

Secondary Outcome ◽

Diagnostic Efficiency ◽

Sample Collection ◽

Crc Screening ◽

Significant Difference ◽

Immunochemical Test ◽

Operant Training

Objective: The diagnostic efficiency of the quantitative fecal immunochemical test (qFIT) has large variations in colorectal cancer (CRC) screening. We aimed to explore whether the practical sample collection operant training could improve the diagnostic accuracy of the qFIT in CRC screening.Methods: Moderate-/high-risk individuals aged 50–75 years old were invited to participate in a prospective observational study between July 2020 and March 2021. Participants took a qFIT sample without fecal sample collection operant training in advance and then completed another qFIT sample after the operant training. The primary outcome was the sensitivity and specificity of the qFITs for CRC and advanced colorectal neoplasia (ACRN). The secondary outcome was the difference in the area under the curves (AUCs) and the concentrations of the fecal hemoglobin (Hb) between the qFIT without and after the operant training.Results: Out of 913 patients, 81 (8.9%) patients had ACRN, including 25 (2.7%) patients with CRC. For CRC, the sensitivities of the qFIT without and after the operant training at 10 μg/g were 80.4 and 100.0%, respectively, and the specificities were 90.1 and 88.4%, respectively. For ACRN, the sensitivities were 49.4 and 69.1% and the specificities were 91.7 and 91.3%, respectively. The AUC of the qFIT after the operant training was significantly higher than that without the operant training for CRC (p = 0.027) and ACRN (p = 0.001). After the operant training, the concentration of the fecal Hb was significantly higher than that without the operant training (p = 0.009) for ACRN, but there was no significant difference for CRC (p = 0.367).Conclusion: Practical sample collection operant training improves the diagnostic accuracy of the qFIT, which increases the detection of the low concentrations of fecal Hb. Improving the quality of the sample collection could contribute to the diagnostic efficiency of the qFIT in CRC screening.

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