Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome

ObjectiveThe plasma-based methylated SEPTIN9 (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50–75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.DesignFirstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the “1/1 algorithm”. LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.ResultsDifferential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).ConclusionThese preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case–control study.

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Non-invasive colorectal cancer screening

University of Western Ontario Medical Journal ◽

10.5206/uwomj.v85i2.2231 ◽

2016 ◽

Vol 85 (2) ◽

pp. 29-31

Author(s):

Melissa Holdren ◽

Brittany Deller ◽

Kevin Braden

Keyword(s):

Colorectal Cancer ◽

Developmental Process ◽

Population Based ◽

Adenomatous Polyps ◽

Morbidity And Mortality ◽

Screening Tests ◽

Average Risk ◽

Screening Programs ◽

Asymptomatic Patients ◽

Advanced Adenomas

Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world and is the second most common cause of Canadian cancer-related deaths in men and the third most common in women. Most CRC appears to arise from the gradual development and advancement of colonic adenomatous polyps to cancerous tissue. This developmental process of CRC is the rationale for screening programs which aim to reduce CRC-related morbidity and mortality by early detection and removal of adenomatous polyps, specifically advanced adenomas. Although both the gFOBT and FIT function to detect occult bleeding in asymptomatic patients at average risk for CRC development, the mechanisms of these screening tests are distinct. gFOBT works by detecting the peroxidase activity of heme whereas FIT selectively detects human hemoglobin. The sensitivity in detecting CRC is higher for the FIT, with sensitivity of 0.79 compared to gFOBT with sensitivity of 0.36, they have similar specificities of 0.94 and 0.96, respectively. Currently, both the gFOBT and FIT are strongly recommended across Canada, with all provinces using the FIT, apart from Ontario and Manitoba which currently use the gFOBT to screen asymptomatic patients for CRC. A newer test, the sDNA test, identifies mutations in DNA that are shed by both adenomatous polyps and CRC cells. The sDNA test is more sensitive (0.92 95% CI 0.83-0.98) than both the gFOBT and FIT, however, is less specific and more expensive. Further data surrounding the sDNA test will be required prior to its implementation and recommendation for population based CRC screening in Canada.

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Postcolonoscopy colorectal cancers in average-risk Korean subjects with a normal initial colonoscopy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.526 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 526-526

Author(s):

Han Hee Lee ◽

Hyun Ho Choi ◽

Chun-Hyun Lim ◽

Hyung-Keun Kim ◽

Sung Soo Kim ◽

...

Keyword(s):

Colorectal Cancer ◽

Advanced Adenoma ◽

Colorectal Cancers ◽

Average Risk ◽

Asian Countries ◽

Technical Improvement ◽

Advanced Neoplasia ◽

Adenoma Detection ◽

Advanced Adenomas

526 Background: There are relatively few studies regarding the incidence of postcolonoscopy colorectal cancer (PCCRC) in Asian countries. We evaluated the characteristics of PCCRC in average-risk Korean subjects. Methods: This study included subjects who were ≥ 50 years of age and had undergone a first completed colonoscopy between January 2001 and December 2004, at which no baseline adenoma had been detected, followed by a second colonoscopy 1–5 years later. The incidence and characteristics of advanced neoplasia in these subjects were assessed. Results: A total of 343 subjects underwent follow-up colonoscopy within 5 years. Seventy-three (21.3%) subjects were found to have at least one adenoma upon follow-up colonoscopy. Advanced adenoma was found in eight (2.3%) subjects, and non-advanced adenomas were found in 65 (19.0%). Five patients (1.5%) were diagnosed with invasive CRC following a normal colonoscopy. The putative reason for the PCCRCs was missed lesions in two (40.0%) and new cancer in three (60.0%) cases. Conclusions: The risk of advanced neoplasia (including PCCRCs) within 5 years after a normal baseline colonoscopy in our cohort was not low. Considering that 40% of PCCRCs were attributable to missed lesions, our results emphasize the need for technical improvement of colonoscopic examinations to improve adenoma detection.

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Colorectal Cancer Surveillance after Index Colonoscopy: Guidance from the Canadian Association of Gastroenterology

Canadian Journal of Gastroenterology ◽

10.1155/2013/232769 ◽

2013 ◽

Vol 27 (4) ◽

pp. 224-228 ◽

Cited By ~ 14

Author(s):

Desmond Leddin ◽

Robert Enns ◽

Robert Hilsden ◽

Carlo A Fallone ◽

Linda Rabeneck ◽

...

Keyword(s):

Colorectal Cancer ◽

Task Force ◽

Cancer Surveillance ◽

Screening Tests ◽

Average Risk ◽

Health Care Environment ◽

Canadian Association ◽

The Us ◽

Colonoscopy Surveillance

BACKGROUND: Differences between American (United States [US]) and European guidelines for colonoscopy surveillance may create confusion for the practicing clinician. Under- or overutilization of surveillance colonoscopy can impact patient care.METHODS: The Canadian Association of Gastroenterology (CAG) convened a working group (CAG-WG) to review available guidelines and provide unified guidance to Canadian clinicians regarding appropriate follow-up for colorectal cancer (CRC) surveillance after index colonoscopy. A literature search was conducted for relevant data that postdated the published guidelines.RESULTS: The CAG-WG chose the 2012 US Multi-Society Task Force (MSTF) on Colorectal Cancer to serve as the basis for the Canadian position, primarily because the US approach was the simplest and comprehensively addressed the issue of serrated polyps. Aspects of other guidelines were incorporated where relevant. The CAG-WG recommendations differed from the US MSTF guidelines in three main areas: patients with negative index colonoscopy should be followed-up at 10 years using any of the appropriate screening tests, including colonos-copy, for average-risk individuals; among patients with >10 adenomas, a one-year interval for subsequent colonoscopy is recommended; and for long-term follow-up, patients with low-risk adenomas on both the index and first follow-up procedures can undergo second follow-up colonos-copy at an interval of five to 10 years.DISCUSSION: The CAG-WG adapted the US MSTF guidelines for colonoscopy surveillance to the Canadian health care environment with a few modifications. It is anticipated that the present article will provide unified guidance that will enhance physician acceptance and encourage appropriate utilization of recommended surveillance intervals.

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Preferences of Iranian average risk population for colorectal cancer screening tests

International Journal of Health Care Quality Assurance ◽

10.1108/ijhcqa-08-2017-0151 ◽

2019 ◽

Vol 32 (4) ◽

pp. 677-687

Author(s):

Vajiheh Ramezani_Doroh ◽

Alireza Delavari ◽

Mehdi Yaseri ◽

Sara Emamgholipour Sefiddashti ◽

Ali Akbarisari

Keyword(s):

Colorectal Cancer ◽

Health Status ◽

Discrete Choice ◽

Choice Model ◽

Screening Tests ◽

Average Risk ◽

Risk Population ◽

Content Type ◽

Crc Screening ◽

Complication Risk

Purpose The purpose of this paper is to explore the preferences of the average risk Iranian population for colorectal cancer (CRC) screening tests. Design/methodology/approach A standard stated-preferences method with discrete choice models was used to identify the preferences. Data about socio-demographic status, health status and preferences for CRC screening tests were collected by a structured questionnaire that was completed by 500 people aged 50–75 years. Mixed logit model was used to analyze the preferences. Findings The regression model showed that the test process, pain, place, frequency, preparation, sensitivity, complication risk, mortality rate and cost were the final attributes; that had a statistically significant correlation with the preferences of the people in choosing CRC screening tests. The socio-demographic and health status of participants had no significant correlation with the individuals’ preferences. Practical implications This study provides insight into how different characteristics of a CRC screening test might influence the preferences of individuals about that test. Originality/value This was the first study of this type in Iran to elicit the preferences of the average risk population for CRC screening tests using a discrete choice model.

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Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population

Gut ◽

10.1136/gutjnl-2020-320990 ◽

2020 ◽

Vol 69 (12) ◽

pp. 2244-2255 ◽

Cited By ~ 2

Author(s):

Nicolas Chapelle ◽

Myriam Martel ◽

Esther Toes-Zoutendijk ◽

Alan N Barkun ◽

Marc Bardou

Keyword(s):

Colorectal Cancer ◽

Fruits And Vegetables ◽

Healthy Lifestyle ◽

Mortality Rates ◽

Preliminary Evidence ◽

Dietary Factors ◽

Normal Colonic Mucosa ◽

Average Risk ◽

Level Of Evidence ◽

Incidence And Mortality

Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention—more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, β-carotene and selenium, but is low or very low for all other exposures or interventions.

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An Interventional Study to Improve Colorectal Cancer Screening Knowledge and Health Perceptions among Jordanians' Average Risk Population

The Open Nursing Journal ◽

10.2174/1874434601913010237 ◽

2019 ◽

Vol 13 (1) ◽

pp. 237-248 ◽

Cited By ~ 1

Author(s):

Fuad H. Abuadas ◽

Mohammad H. Abuadas

Keyword(s):

Colorectal Cancer ◽

Intervention Group ◽

Health Perceptions ◽

Control Group ◽

Education Intervention ◽

Average Risk ◽

Convenience Sample ◽

Risk Population ◽

The Mean ◽

Study Participants

Context: Globally, Colorectal Cancer (CRC) is the second most commonly occurring cancer in women and the third most commonly occurring cancer in men. Aims: This study was conducted to investigate the current levels of Jordanians' CRC knowledge and health perceptions; and to test the effects of a health education intervention on them. Settings and Design: A descriptive quasi-experimental design was used to recruit a convenience sample of 197 Jordanian adult participants from two governmental hospitals in Amman. Methods and Material: A rolling enrolment strategy was used to randomly assign participants into intervention (n=98) and control (n=99) groups. An education intervention included a 1-hour Power Point presentation about CRC. Results: The mean knowledge scores were (6.51±1.60) and (6.91± 1.83) for females and males, respectively. The mean of the knowledge level in the intervention group subsequent to the intervention was significantly higher than that for the control group. More than half of the study participants (53.8%) did not believe they were susceptible to CRC, while about one third (37.4%) of the participants believed that CRC is a severe disease. 42.2% of study participants believed there were barriers preventing them from participating in CRC screening. The most frequently perceived barrier among them was the cost of screening tests. The means of the perceived susceptibility and severity subscales of the intervention group was significantly higher than that of the control group. Conclusion: Correcting the knowledge gap and improper health perceptions toward CRC could play an important role in facilitating early detection as a primary prevention measure. Findings may enhance health strategies to better address the needs of the average-risk population.

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Point Sensitivity of the Multi-target Stool DNA Test for Colorectal Cancer Screening in Individuals Ages 45-49 Years

10.1101/2020.09.01.20177568 ◽

2020 ◽

Author(s):

Michael Domanico ◽

Sandra Statz ◽

Emily Weiser ◽

Barry M Berger ◽

Paul J Limburg

Keyword(s):

Colorectal Cancer ◽

Precancerous Lesions ◽

Screening Tests ◽

Average Risk ◽

Small Pilot Study ◽

Data Annotation ◽

Test Sensitivity ◽

Link Type ◽

Stool Samples ◽

Stool Dna

Background: Most colorectal cancer (CRC) screening tests have not been rigorously studied in younger age groups. Aims: To estimate sensitivity of the multi-target stool DNA (mt-sDNA) test in patients ages 45-49 years. Methods: We identified archived stool samples (Exact Sciences; Madison, WI) from individuals ages 45-49 years who had completed an index colonoscopy and had confirmed diagnoses of CRC or advanced precancerous lesions (APL; defined as high-grade dysplasia, greater than 25% villous morphology, or greater than or equal to 1 cm in size [conventional adenoma or serrated lesion]). Data annotation referent to potential CRC risk factors, other than age, was limited. Stool samples were collected at least 7 days after the index colonoscopy, prior to lesion excision or treatment. Stool samples were processed and analyzed per established laboratory protocols for the mt-sDNA assay. Mt-sDNA test sensitivity for CRC, APL, and CRC+APL was estimated from the available sample set. Samples were collected from 2010-2013 (NCT01260168) and 2014-2017 (NCT02503631), with sample testing and analysis in 2019. Results: Stool samples were analyzed from 19 eligible subjects, 13 with CRC and 6 with APL. Estimated mt-sDNA test sensitivity for CRC, APL, and CRC+APL were 92%, 83%, and 89%, respectively. Conclusions: In this small pilot study using existing archived stool samples from subjects ages 45-49 years, mt-sDNA test sensitivity was similar to previously reported estimates for individuals ages greater than or equal to 50 years. These results support the application of mt-sDNA screening to average-risk patients beginning at age 45 years. Larger studies are needed to confirm and extend these findings.

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Analysis of A 6-Mirna Signature in Serum from Colorectal Cancer Screening Participants as Non-Invasive Biomarkers for Advanced Adenoma and Colorectal Cancer Detection

Cancers ◽

10.3390/cancers11101542 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1542 ◽

Cited By ~ 4

Author(s):

María Marcuello ◽

Saray Duran-Sanchon ◽

Lorena Moreno ◽

Juan José Lozano ◽

Luis Bujanda ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Detection ◽

Diagnostic Performance ◽

Colorectal Neoplasia ◽

Precancerous Lesion ◽

Advanced Adenoma ◽

Average Risk ◽

Mirna Signature ◽

Crc Screening ◽

Non Invasive

Early detection of colorectal cancer (CRC) and its precancerous lesion, advanced adenomas (AA), is critical to improve CRC incidence and prognosis. Circulating microRNAs (miRNAs or miR) are promising non-invasive biomarkers for cancer detection. Our previous results showed that a plasma 6-miRNA signature (miR-15b-5p, miR-18a-5p, miR-29a-3p, miR-335-5p, miR-19a-3p and miR-19b-3p) could distinguish between CRC or AA and healthy individuals (controls). However, its diagnostic performance in serum is unknown. In this exploratory study we aim to evaluate the diagnostic performance of the 6-miRNA signature in serum samples in a cohort of individuals participating in Barcelona’s CRC Screening Programme. We prospectively collected serums from 264 faecal immunochemical test (FIT)-positive participants and total RNA was extracted. Finally, 213 individuals (CRC, 59, AA, 74, controls, 80) were included. MiRNA expression was quantified by real-time RT-qPCR and data analysis was performed by logistic regression. Faecal hemoglobin concentration (f(Hb)) from FIT of the same individuals was also considered. As previously described in plasma, serum from patients with AA or CRC presented significant differences in the 6-miRNA signature compared to controls. Moreover, when combined with f(Hb), the final signature showed high discriminative capacity to distinguish CRC from controls (area under the curve (AUC) = 0.88), and even AA (AUC = 0.81) that otherwise are poorly detected if we only consider f(Hb) (AUC = 0.64). Addition of the serum 6-miRNA signature to quantitative f(Hb) show high accuracy to detect patients with advanced colorectal neoplasia in average-risk individuals. A combination of these two non-invasive methods could be a good strategy to improve diagnostic performances of current CRC screening programmes.

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Sensitivity of second-generation blood-based methylated Septin9 assay for early-stage colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.419 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 419-419 ◽

Cited By ~ 1

Author(s):

Gunter Weiss ◽

Anne Fassbender ◽

Thomas Koenig ◽

Reimo Tetzner

Keyword(s):

Colorectal Cancer ◽

Real Time ◽

Real Time Pcr ◽

Early Stage ◽

Screening Colonoscopy ◽

Molecular Diagnostic ◽

Control Group ◽

Average Risk ◽

Early Stage Disease ◽

Crc Screening

419 Background: Early detection of colorectal cancer (CRC) has been shown to decrease mortality, although compliance to CRC screening is low. Availability of a blood-based test is expected to improve CRC screening compliance. Specific detection of CRC using the Septin9 biomarker (mSEPT9) in a large prospective trial of an average-risk CRC screening population exhibited 67% sensitivity for CRC with 88% specificity. Laboratory-developed tests detecting mSEPT9 in plasma are now available in North America and a 2nd generation molecular diagnostic blood test for mSEPT9 is available as a CE-marked kit in Europe. The current research evaluated the clinical performance of the 2nd generation mSEPT9 assay. Methods: Bisulfite-converted DNA (bisDNA) was prepared from 3.5 mL human plasma using the 2ndgeneration plasma DNA preparation kit. Resulting bisDNA was analyzed in triplicate on the ABI7500 Fast Dx (Life Technologies, Inc.) using proprietary HeavyMethyl real-time PCR technology for mSEPT9 and the 2nd generation real-time PCR kit. In a case – control design, plasma from 98 CRC patients (n = 87 stages I - III) and 99 age-matched, colonoscopy-verified normal individuals were processed with the mSEPT9 assay. In addition, plasma from 150 prospectively enrolled average risk individuals scheduled for screening colonoscopy was tested. mSEPT9 was qualitatively analyzed such that any detection of mSEPT9 in a PCR was called “positive”. Results: The revised mSEPT9 assay exhibited 95% sensitivity (95% CI: 89-98%) for CRC. Sensitivity for stage I was 89% (95% CI: 72-96%, n = 27) and sensitivity for stage II was 93% (95% CI: 78-98%, n = 29). The control group was positive at a rate of 16% (95% CI: 10-25%). Specificity of the mSEPT9 assay in the screening cohort was 85% (95% CI: 78-89%). Conclusions: The 2nd generation mSEPT9 assay demonstrated improved sensitivity for CRC without significant impact on specificity. The enhanced design and robustness of the assay will further facilitate its standardized use in routine laboratory settings. Finally, the increased sensitivity of the revised mSEPT9 assay improves the detection of early stage disease and demonstrates the feasibility of a blood-based CRC screening technology.

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Accurate Five-category Classification for Colorectal Cancer Using Gut Microbiome 16S rRNA Sequencing

10.21203/rs.3.rs-763700/v1 ◽

2021 ◽

Author(s):

Liying Zhang ◽

Jiaqi Zhu ◽

Qiutao Ding ◽

Yanqi Huang ◽

Hongbo Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

16S Rrna ◽

Gut Microbiome ◽

Large Scale ◽

Operational Taxonomic Unit ◽

16S Rrna Sequencing ◽

Screening Tests ◽

Advanced Adenoma ◽

Sequencing Data ◽

Rrna Sequencing

Abstract The association between the gut microbiome and the five stages of colorectal cancer (CRC) (healthy, polyposis, nonadvanced adenoma, advanced adenoma, and cancer) remains unclear. We performed 16S rRNA sequencing of the V3-V4 amplicon from 999 samples from subjects at various stages of CRC development and constructed an accurate predictive random forest model for CRC development. In the testing set, our five-category CRC prediction classifier had accuracies of 0.84 and 0.74 using the relative operational taxonomic unit (OTU) abundances and relative genus abundances, respectively. Specifically, the OTU-based classifier had a sensitivity of 0.97 and specificity of 0.97 for CRC samples, and the genus-based classifier had a sensitivity of 0.97 and specificity of 0.95 for CRC samples. Meanwhile, the gut microbiota was found to differ at all stages of CRC development. The differential abundances of closely related bacteria were used to accurately classify the five stages of CRC development. Additionally, both unannotated and annotated OTUs played important roles in classifier modelling. Our work not only provides valuable 16S rRNA sequencing data from patients and healthy individuals on a large scale but also identifies reproducible gut microbiome biomarkers for CRC staging and highlights their potential applications as noninvasive microbiome biomarkers for diagnosis and as predictive CRC screening tests.

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