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Alampritis G, Thoukididou SN, Ramos M, Georgiou P, Kalofonou M, Simillis C. Diagnostic value of genetic and epigenetic biomarker panels for colorectal cancer detection: a systematic review. Int J Colorectal Dis 2025; 40:125. [PMID: 40402271 PMCID: PMC12098509 DOI: 10.1007/s00384-025-04904-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE Exploration of effective screening methods is imperative to improve current screening for colorectal cancer (CRC). Our aim was to systematically search the literature to identify and assess the diagnostic accuracy of both genetic and epigenetic biomarker panels for CRC detection using liquid biopsies for circulating tumour DNA (ctDNA) from stool, blood, or urine. METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) with searches in Medline, Embase, CENTRAL, and Web Of Science from inception up to March 20, 2025, using pre-defined keywords. Study quality assessment was performed using QUADAS-2 tool (Quality Assessment for Diagnostic Accuracy Studies 2). Primary and secondary outcomes were panel performance (sensitivity and specificity) for CRC, advanced precancerous lesions (APL), and staging of disease. RESULTS Forty-four studies were included. Exceptional performance for both CRC (sensitivity and specificity) and APL (sensitivity) was displayed by biomarker panels including methylated SDC2 with methylated SFRP1/2 (CRC: 91.5%/97.3%, APL: 89.2%) or methylated TFPI2 (CRC: 94.9%/98.1%, APL: 100%), and a 5-biomarker panel of mutational targets APC, Bat-26, KRAS, L-DNA, and p53 (CRC: 91.0%/93.0%, APL: 82.0%). Suboptimal APL sensitivities up to 57.0% were exhibited by Cologuard and variant panels (including KRAS, methylated BMP3, methylated NDRG4, FIT), and 47.8% for combinations including methylated SEPT9. CONCLUSIONS High-performance, candidate ctDNA biomarker panels with exceptional diagnostic accuracy for both CRC and APL have been identified. Further work should focus on the development of large-scale studies to justify their clinical implementation.
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Affiliation(s)
- Georgios Alampritis
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Sarah Nohelia Thoukididou
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Maria Ramos
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Pantelis Georgiou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Melpomeni Kalofonou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Constantinos Simillis
- Department of Surgery, University of Cambridge, Cambridge, UK.
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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2
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Melson J. Application of the Colorectal Cancer (CRC) Screening Guiding Principles for Non-invasive Testing to Multi-target Stool DNA: A Case Study. Dig Dis Sci 2025; 70:1676-1682. [PMID: 39971827 DOI: 10.1007/s10620-025-08860-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/09/2025] [Indexed: 02/21/2025]
Abstract
A significant lack of participation in colorectal cancer (CRC) screening programs in the United States limits the impact of screening to reduce morbidity and mortality. Recently a group of experts in CRC screening defined the Guiding Principles for Noninvasive Testing (GPNIT). GPNIT pathway is intended to serve as a step by step guide for study design to ultimately lead to implementation and integration of a potentially clinically appropriate CRC screening test. Multi-target stool DNA (MT-sDNA) test usage for CRC screening has increased significantly recently in the United States. Here, the key studies in the development of MT-sDNA as an emerging CRC screening test are placed in context of the GPNIT pathway for CRC screening test development. This case study is meant to be instructive for future test development in CRC screening to achieve ultimately clinically relevant future tests and improve the efficacy of CRC screening.
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Affiliation(s)
- Joshua Melson
- Division of Gastroenterology, Department of Internal Medicine, Banner University Medical Center, University of Arizona Cancer Center, Tucson, AZ, USA.
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3
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Newell ME, Babbrah A, Aravindan A, Rathnam R, Halden RU. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life (Basel) 2025; 15:482. [PMID: 40141826 PMCID: PMC11943902 DOI: 10.3390/life15030482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).
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Affiliation(s)
- Melanie Engstrom Newell
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
| | - Ayesha Babbrah
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Anumitha Aravindan
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Raj Rathnam
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Rolf U. Halden
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85281, USA
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Iyer PG, Slettedahl SW, Mahoney DW, Giakoumopoulos M, Olson MC, Krockenberger M, Taylor WR, Foote P, Berger C, Leggett C, Wu TT, Antpack E, Falk GW, Ginsberg GG, Abrams JA, Lightdale CJ, Ramirez F, Kahn A, Wolfsen H, Konda V, Trindade AJ, Kisiel JB. Algorithm Training and Testing for a Nonendoscopic Barrett's Esophagus Detection Test in Prospective Multicenter Cohorts. Clin Gastroenterol Hepatol 2024; 22:1596-1604.e4. [PMID: 38513982 PMCID: PMC11272429 DOI: 10.1016/j.cgh.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND & AIMS Endoscopic Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Nonendoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort. METHODS Algorithm training and test samples were from 2 prospective multicenter cohorts. All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); control subjects had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set. RESULTS Training (N = 352) and test (N = 125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI, 68%-94%) at 90% (79%-98%) specificity and 88% (78%-94%) sensitivity at 84% (70%-93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long- and short-segment BE, respectively. Sensitivity for BE with high-grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively. CONCLUSIONS A locked 3-MDM panel algorithm for BE/EAC detection using a nonendoscopic CCD demonstrated excellent sensitivity for high-risk BE cases in independent validation samples. (Clinical trials.gov: NCT02560623, NCT03060642.).
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Affiliation(s)
- Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Seth W Slettedahl
- Division of Clinical Trials, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Douglas W Mahoney
- Division of Clinical Trials, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | | | | | | | - William R Taylor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick Foote
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Calise Berger
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Cadman Leggett
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tsung-Teh Wu
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | - Eduardo Antpack
- Department of Surgery, Mayo Clinic Health System, Austin, Minnesota
| | - Gary W Falk
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Gregory G Ginsberg
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Julian A Abrams
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York
| | - Charles J Lightdale
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York
| | - Francisco Ramirez
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona
| | - Allon Kahn
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona
| | - Herbert Wolfsen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Vani Konda
- Division of Gastroenterology and Hepatology, Baylor University Medical Center, Dallas, Texas
| | - Arvind J Trindade
- Division of Gastroenterology and Hepatology, Zucker School of Medicine at Hofstra/Northwell, Long Island Jewish Medical Center, New Hyde Park, New York
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Galeș LN, Păun MA, Anghel RM, Trifănescu OG. Cancer Screening: Present Recommendations, the Development of Multi-Cancer Early Development Tests, and the Prospect of Universal Cancer Screening. Cancers (Basel) 2024; 16:1191. [PMID: 38539525 PMCID: PMC10969110 DOI: 10.3390/cancers16061191] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/08/2024] [Accepted: 03/15/2024] [Indexed: 11/11/2024] Open
Abstract
Cancer continues to pose a considerable challenge to global health. In the search for innovative strategies to combat this complex enemy, the concept of universal cancer screening has emerged as a promising avenue for early detection and prevention. In contrast to targeted approaches that focus on specific populations or high-risk individuals, universal screening seeks to cast a wide net to detect incipient malignancies in different demographic groups. This paradigm shift in cancer care underscores the importance of comprehensive screening programs that go beyond conventional boundaries. As our understanding of the complex molecular and genetic basis of cancer deepens, the need to develop comprehensive screening methods becomes increasingly apparent. In this article, we look at the rationale and potential benefits of universal cancer screening.
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Affiliation(s)
- Laurenția Nicoleta Galeș
- Department of Oncology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.N.G.); (R.M.A.); (O.G.T.)
- Department of Medical Oncology II, Prof. Dr. Al. Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Mihai-Andrei Păun
- Department of Radiotherapy II, Prof. Dr. Al. Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Rodica Maricela Anghel
- Department of Oncology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.N.G.); (R.M.A.); (O.G.T.)
- Department of Radiotherapy II, Prof. Dr. Al. Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Oana Gabriela Trifănescu
- Department of Oncology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.N.G.); (R.M.A.); (O.G.T.)
- Department of Radiotherapy II, Prof. Dr. Al. Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
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Wang H, Cao X, Meng P, Zheng C, Liu J, Liu Y, Zhang T, Li X, Shi X, Sun X, Zhang T, Zuo H, Wang Z, Fu X, Li H, Zheng H. Machine learning-based identification of colorectal advanced adenoma using clinical and laboratory data: a phase I exploratory study in accordance with updated World Endoscopy Organization guidelines for noninvasive colorectal cancer screening tests. Front Oncol 2024; 14:1325514. [PMID: 38463224 PMCID: PMC10921227 DOI: 10.3389/fonc.2024.1325514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 02/05/2024] [Indexed: 03/12/2024] Open
Abstract
Objective The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. Methods We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. Results The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. Conclusion The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons.
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Affiliation(s)
- Huijie Wang
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Xu Cao
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Ping Meng
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Caihua Zheng
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Jinli Liu
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Yong Liu
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Tianpeng Zhang
- Department of Anus & Intestine Surgery, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Xiaofang Li
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Xiaoyang Shi
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Xiaoxing Sun
- Department of Endoscopy, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
| | - Teng Zhang
- Institute of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Haiying Zuo
- Graduate School, Hebei North University, Zhangjiakou, China
| | - Zhichao Wang
- Graduate School, Hebei North University, Zhangjiakou, China
| | - Xin Fu
- Research and Development Department, Wuhan Metware Biotechnology Co., Ltd, Wuhan, China
| | - Huan Li
- Research and Development Department, Wuhan Metware Biotechnology Co., Ltd, Wuhan, China
| | - Huanwei Zheng
- Department of Gastroenterology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, China
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Ye J, Zhang J, Ding W. DNA methylation modulates epigenetic regulation in colorectal cancer diagnosis, prognosis and precision medicine. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:34-53. [PMID: 38464391 PMCID: PMC10918240 DOI: 10.37349/etat.2024.00203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/11/2023] [Indexed: 03/12/2024] Open
Abstract
Colorectal cancer (CRC) is a multifaceted disease influenced by the interplay of genetic and environmental factors. The clinical heterogeneity of CRC cannot be attributed exclusively to genetic diversity and environmental exposures, and epigenetic markers, especially DNA methylation, play a critical role as key molecular markers of cancer. This review compiles a comprehensive body of evidence underscoring the significant involvement of DNA methylation modifications in the pathogenesis of CRC. Moreover, this review explores the potential utility of DNA methylation in cancer diagnosis, prognostics, assessment of disease activity, and prediction of drug responses. Recognizing the impact of DNA methylation will enhance the ability to identify distinct CRC subtypes, paving the way for personalized treatment strategies and advancing precision medicine in the management of CRC.
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Affiliation(s)
- Jingxin Ye
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Gastroenterology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian 223800, Jiangsu Province, China
| | - Jianfeng Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Weifeng Ding
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Voss JK, Ebner DW, Burger KN, Mahoney DW, Devens ME, Lowrie KL, Kisiel JB. Multitarget Stool DNA Testing Has High Positive Predictive Value for Colorectal Neoplasia on the Second Round of Testing. Clin Gastroenterol Hepatol 2023; 21:2399-2406. [PMID: 36621751 PMCID: PMC10323033 DOI: 10.1016/j.cgh.2022.12.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/08/2022] [Accepted: 12/11/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Multitarget stool DNA (mt-sDNA) testing is a stool-based screening test for colorectal cancer (CRC). In a single instance of testing, the pivotal Food and Drug Administration-approval study (NCT01397747) found that 16% of mt-sDNA tests were positive, and the positive predictive value (PPV) for CRC or advanced precursor lesions (APL) was 27.3%. We aimed to examine real-world longitudinal performance by determining the test-positive rate and PPV of mt-sDNA on the second round of testing. METHODS Colonoscopy and pathology reports were reviewed retrospectively for patients with a negative mt-sDNA on the first round of screening and a positive mt-sDNA on the second round. The test-positivity rate and PPV for CRC, APL, and any colorectal neoplasia were calculated for the second mt-sDNA and compared with baseline PPVs from a previously published cohort of patients from our institution who tested positive on the first round of screening. RESULTS A total of 2758 patients completed a second test at a median of 3.2 years after the first test. Of these, 422 (15%) had a positive second mt-sDNA. The PPV was 0.25% for CRC, 24% for APL, and 67% for any colorectal neoplasia. There was no significant difference in PPV on the second mt-sDNA test compared with the first round (24% vs 28% for APL; P = .12). CONCLUSIONS mt-sDNA test positive rate and PPV were similar between the first and second rounds of screening. These observations confirm the utility of a second round of mt-sDNA screening and may inform estimates of mt-sDNA effectiveness for CRC screening.
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Affiliation(s)
- Jordan K Voss
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Derek W Ebner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Keli N Burger
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Douglas W Mahoney
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Mary E Devens
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Kari L Lowrie
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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9
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Kortlever T, de Klaver W, van der Vlugt M, Meijer G, Dekker E, Bossuyt P. Cross-sectional risk models using quantitative fecal hemoglobin in colorectal cancer screening: a systematic review. Expert Rev Mol Diagn 2023; 23:1221-1232. [PMID: 37930046 DOI: 10.1080/14737159.2023.2279607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 10/20/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION Fecal Immunochemical Testing (FIT) is a central tool in colorectal cancer (CRC) screening. To improve the selection of individuals for colonoscopy, risk models combining FIT with additional CRC risk factors have been developed. This systematic review aims to provide an overview of the current noninvasive FIT-based risk models for CRC screening to facilitate future implementation. METHODS We performed a systematic literature search for risk models that combined quantitative fecal hemoglobin with clinical data or noninvasive biomarkers and that were intended for CRC screening. Risk of bias was assessed using the PROBAST tool. RESULTS Twenty risk models reported across 29 publications were included. The overall risk of bias was high. In studies that compared risk models to FIT, 11/12 (92%) risk models had a significantly higher c-statistic than FIT only. 16/20 risk models (80%) had not been externally validated and only one model has been implemented so far. CONCLUSION FIT-based risk models have the potential to improve the yield of CRC screening. Unfortunately, all included publications had a high risk of bias and most risk models have not yet been externally validated. The prospect of improved CRC screening with risk models should encourage more rigorous evaluation in existing screening programs.
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Affiliation(s)
- Tim Kortlever
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam, the Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands
| | - Willemijn de Klaver
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam, the Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Manon van der Vlugt
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam, the Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands
| | - Gerrit Meijer
- Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam, the Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands
| | - Patrick Bossuyt
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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10
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Bakkum-Gamez JN, Sherman ME, Slettedahl SW, Mahoney DW, Lemens MA, Laughlin-Tommaso SK, Hopkins MR, VanOosten A, Shridhar V, Staub JK, Cao X, Foote PH, Clarke MA, Burger KN, Berger CK, O'Connell MC, Doering KA, Podratz KC, DeStephano CC, Schoolmeester JK, Kerr SE, Wentzensen N, Taylor WR, Kisiel JB. Detection of endometrial cancer using tampon-based collection and methylated DNA markers. Gynecol Oncol 2023; 174:11-20. [PMID: 37141817 PMCID: PMC10330802 DOI: 10.1016/j.ygyno.2023.04.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 04/16/2023] [Accepted: 04/16/2023] [Indexed: 05/06/2023]
Abstract
OBJECTIVE Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. METHODS For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. RESULTS Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91). CONCLUSION Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted.
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Affiliation(s)
- Jamie N Bakkum-Gamez
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America.
| | - Mark E Sherman
- Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States of America
| | - Seth W Slettedahl
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America
| | - Douglas W Mahoney
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America
| | - Maureen A Lemens
- Surgery Research, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, United States of America
| | - Shannon K Laughlin-Tommaso
- Department of Obstetrics and Gynecology, Division of Gynecology, Mayo Clinic, Rochester, MN, United States of America
| | - Matthew R Hopkins
- Department of Obstetrics and Gynecology, Division of Gynecology, Mayo Clinic, Rochester, MN, United States of America
| | - Ann VanOosten
- Surgery Research, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, United States of America
| | - Viji Shridhar
- Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Julie K Staub
- Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Xiaoming Cao
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Patrick H Foote
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Megan A Clarke
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
| | - Kelli N Burger
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Calise K Berger
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Maria C O'Connell
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Karen A Doering
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Karl C Podratz
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America
| | - Christopher C DeStephano
- Department of Obstetrics and Gynecology, Division of Minimally Invasive Gynecology, Mayo Clinic, Jacksonville, FL, United States of America
| | - J Kenneth Schoolmeester
- Department of Laboratory Medicine and Pathology, Anatomic Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Sarah E Kerr
- Hospital Pathology Associates, Minneapolis, MN, United States of America
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
| | - William R Taylor
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - John B Kisiel
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
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11
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Ebner DW, Burger KN, Broderick B, Mahoney DW, Kellogg TA, Acosta A, Kisiel JB. Positive Predictive Value for Multitarget Stool DNA After Bariatric and Metabolic Surgery. GASTRO HEP ADVANCES 2023; 2:902-910. [PMID: 37876832 PMCID: PMC10597571 DOI: 10.1016/j.gastha.2023.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 06/16/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND AND AIMS Bariatric and metabolic surgery (BMS) may adversely affect noninvasive stool tests for colorectal cancer (CRC) screening through several mechanisms. Multitarget stool DNA (mt-sDNA) is approved for CRC screening; however, performance in post-BMS patients is unknown. As the rates of BMS are anticipated to increase with rising incidence of obesity, it is important to evaluate mt-sDNA test performance among these patients. METHODS In a multisite academic and community-based practice, we obtained mt-sDNA results from 10/2014 to 12/2019 through electronic records and an institutional BMS registry. Average CRC risk patients with BMS prior to a positive mt-sDNA underwent a detailed chart review. Follow-up colonoscopy findings were compared to those among BMS patients screened with colonoscopy alone and a historical cohort of patients without BMS, screened by mt-sDNA. The primary study endpoint was the positive predictive value (PPV) for advanced colorectal neoplasia. RESULTS Among 336 average-risk patients who had mt-sDNA after BMS, mt-sDNA was positive in 49 (14.6%), 47/49 (96%) underwent follow-up colonoscopy, and the PPV for advanced neoplasia was 12/47 (25.5%). This is similar to the PPV for advanced colorectal neoplasia (425/1542, 28%) in a historical cohort of persons without prior BMS, screened by mt-sDNA at our center (P = .86). Among those who had prior BMS, the rate of advanced neoplasia was higher after mt-sDNA compared to screening colonoscopy alone. CONCLUSION Despite anatomic and physiologic mechanisms that could alter blood or DNA content in stool, BMS does not appear to adversely affect the PPV of mt-sDNA.
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Affiliation(s)
- Derek W. Ebner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Kelli N. Burger
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - Brendan Broderick
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - Douglas W. Mahoney
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota
| | - Todd A. Kellogg
- Division of Endocrine & Metabolic Surgery, Mayo Clinic, Rochester, USA Minnesota
| | - Andres Acosta
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John B. Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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12
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Ameen S, Wong MC, Turner P, Yee KC. Improving colorectal cancer screening - consumer-centred technological interventions to enhance engagement and participation amongst diverse cohorts. Clin Res Hepatol Gastroenterol 2023; 47:102064. [PMID: 36494072 DOI: 10.1016/j.clinre.2022.102064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 09/30/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
The current "Gold Standard" colorectal cancer (CRC) screening approach of faecal occult blood test (FOBT) with follow-up colonoscopy has been shown to significantly improve morbidity and mortality, by enabling the early detection of disease. However, its efficacy is predicated on high levels of population participation in screening. Several international studies have shown continued low rates of screening participation, especially amongst highly vulnerable lower socio-economic cohorts, with minimal improvement using current recruitment strategies. Research suggests that a complex of dynamic factors (patient, clinician, and the broader health system) contribute to low citizen engagement. This paper argues that the challenges of screening participation can be better addressed by (1) developing dynamic multifaceted technological interventions collaboratively across stakeholders using human-centered design; (2) integrating consumer-centred artificial intelligence (AI) technologies to maximise ease of use for CRC screening; and (3) tailored strategies that maximise population screening engagement, especially amongst the most vulnerable.
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Affiliation(s)
- Saleem Ameen
- College of Health and Medicine, University of Tasmania, Hobart 7000, Tasmania, Australia.
| | - Ming Chao Wong
- College of Sciences and Engineering, University of Tasmania, Hobart 7000, Tasmania, Australia
| | - Paul Turner
- College of Sciences and Engineering, University of Tasmania, Hobart 7000, Tasmania, Australia
| | - Kwang Chien Yee
- College of Health and Medicine, University of Tasmania, Hobart 7000, Tasmania, Australia
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13
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Influence of Unequal Amplification of Methylated and Non-Methylated Template on Performance of Pyrosequencing. Genes (Basel) 2022; 13:genes13081418. [PMID: 36011328 PMCID: PMC9407541 DOI: 10.3390/genes13081418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 12/03/2022] Open
Abstract
Pyrosequencing is one of the technologies widely used for quantitative methylation assessment. The protocol of pyrosequencing experiment consists of PCR amplification of a locus of interest and subsequent sequencing via synthesis of the amplified PCR product. As the PCR in this protocol utilizes one primer set for the amplification of a template originating from both methylated and non-methylated versions of the analysed locus, the unequal amplification of one of the templates may affect the methylation level assessment by pyrosequencing. We have investigated whether the unequal amplification of one of the templates challenges the quantitative properties of the pyrosequencing technology. Our results show that the sensitivity and dynamic range of pyrosequencing can be significantly affected by unequal amplification of the methylated and non-methylated version of the locus of interest in an assay specific manner. Thus, the assessment of the effect of unequal template amplification on the performances of the specific pyrosequencing assay is necessary before using the assay either in research or especially in diagnostic settings.
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15
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Epigenetic insights in the diagnosis, prognosis, and treatment selection in CRC, an updated review. Mol Biol Rep 2022; 49:10013-10022. [PMID: 35727475 DOI: 10.1007/s11033-022-07569-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 05/05/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM The gradual accumulation of genetic and epigenetic alterations can lead to the development of colorectal cancer. In the last decade much research has been done to discover how methylation as an epigenetic alteration leads to carcinogenesis. While Methylation is a biological process, it can influence gene expression by affecting the promoter activity. This article reviews the role of methylation in critical pathways in CRC. METHODS In this study using appropriate keywords, all research and review articles related to the role of methylation on different cancers were collected and analyzed. Also, existing information on methylation detection methods and therapeutic sensitivity or resistance due to DNA methylation were reviewed. RESULTS The results of this survey revealed that while Methylation is a biological process, it can influence gene expression by affecting the promoter activity. Promoter methylation is associated with up or downregulation of genes involved in critical pathways, including cell cycle, DNA repair, and cell adherence. Hence promoter methylation can be used as a molecular tool for early diagnosis, improving treatment, and predicting treatment resistance. CONCLUSION Current knowledge on potential methylation biomarkers for diagnosis and prognoses of CRC has also been discussed. Our survey proposes that a multi-biomarker panel is more efficient than a single biomarker in the early diagnosis of CRC.
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16
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Marinelli LM, Kisiel JB, Slettedahl SW, Mahoney DW, Lemens MA, Shridhar V, Taylor WR, Staub JK, Cao X, Foote PH, Burger KN, Berger CK, O'Connell MC, Doering KA, Giakoumopoulos M, Berg H, Volkmann C, Solsrud A, Allawi HT, Kaiser M, Vaccaro AM, Albright Crawford C, Moehlenkamp C, Shea G, Deist MS, Schoolmeester JK, Kerr SE, Sherman ME, Bakkum-Gamez JN. Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility. Gynecol Oncol 2022; 165:568-576. [PMID: 35370009 PMCID: PMC9133226 DOI: 10.1016/j.ygyno.2022.03.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. RESULTS Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.
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Affiliation(s)
- Lisa M Marinelli
- Department of Pathology and Area Laboratory Services, San Antonio Military Medical Center, San Antonio, TX, United States of America
| | - John B Kisiel
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Seth W Slettedahl
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America
| | - Douglas W Mahoney
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America
| | - Maureen A Lemens
- Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America
| | - Vijayalakshmi Shridhar
- Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - William R Taylor
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Julie K Staub
- Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Xiaoming Cao
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Patrick H Foote
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Kelli N Burger
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America
| | - Calise K Berger
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Maria C O'Connell
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | - Karen A Doering
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America
| | | | - Hannah Berg
- Exact Sciences, Madison, WI, United States of America
| | | | - Adam Solsrud
- Exact Sciences, Madison, WI, United States of America
| | | | | | | | | | | | - Gracie Shea
- Exact Sciences, Madison, WI, United States of America
| | | | - J Kenneth Schoolmeester
- Department of Laboratory Medicine and Pathology, Anatomic Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Sarah E Kerr
- Hospital Pathology Associates, Minneapolis, MN, United States of America
| | - Mark E Sherman
- Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida, United States of America
| | - Jamie N Bakkum-Gamez
- Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America.
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17
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Anand S, Liang PS. A Practical Overview of the Stool DNA Test for Colorectal Cancer Screening. Clin Transl Gastroenterol 2022; 13:e00464. [PMID: 35383606 PMCID: PMC9038502 DOI: 10.14309/ctg.0000000000000464] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/08/2021] [Indexed: 11/20/2022] Open
Abstract
The multitarget stool DNA test with fecal immunochemical test (sDNA-FIT) is recommended by all major US guidelines as an option for colorectal cancer screening. It is approved by the Food and Drug Administration for use in average-risk individuals aged 45 years and older. The sDNA-FIT tests for 11 biomarkers, including point mutations in KRAS, aberrant methylation in NDRG4 and BMP3, and human hemoglobin. Patients collect a stool sample at home, send it to the manufacturer's laboratory within 1 day, and the result is reported in approximately 2 weeks. Compared with FIT, sDNA-FIT has higher sensitivity but lower specificity for colorectal cancer, which translates to a higher false-positive rate. A unique feature of sDNA-FIT is the manufacturer's comprehensive patient navigation system, which operates 24 hours a day and provides active outreach for patient education and reminders in the first month after a test is ordered. Retesting is recommended every 1-3 years, although the optimal testing interval has not yet been determined empirically. The cost of sDNA-FIT is $681 without insurance, but Medicare and most private insurers cover it with no copay or deductible.
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Affiliation(s)
- Sanya Anand
- SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Peter S. Liang
- NYU Langone Health, VA New York Harbor Health Care System, New York, New York, USA.
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18
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Dolatkhah R, Dastgiri S, Jafarabadi MA, Abdolahi HM, Somi MH. Diagnostic Accuracy of Multitarget Stool DNA Testing for Colorectal Cancer Screening: A Systematic Review and Meta-analysis. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:753-766. [PMID: 35101601 DOI: 10.1016/j.gastrohep.2022.01.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/18/2022] [Accepted: 01/21/2022] [Indexed: 01/11/2023]
Abstract
This study aimed to collect and summarize test data and conduct a meta-analysis, with respect to the Multitarget Stool DNA test sensitivity and specificity, compared to colonoscopy. All manuscripts were screened for eligibility according to inclusion criteria. Participants were a normal population at an average risk of developing CRC. Intervention was Stool based and DNA panel tests compared with colonoscopy, and outcome was detection of CRC and any pre-cancerous lesions. Inter-study and inconsistency (using the I-squared test) were assessed. Meta-analyses of the Mt-sDNA test showed a combined sensitivity of 89%, 51%, and 76% for the detection of CRC, advanced adenoma (AA), and combined CRC and AA, respectively. The overall specificity was 91%, 89%, and 90% for the detection of CRC, AA, and combined CRC and AA, respectively. Mt-sDNA had significantly acceptable diagnostic accuracy for CRC and AA diagnosis, but still has lower sensitivity and specificity than colonoscopy.
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Affiliation(s)
- Roya Dolatkhah
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Saeed Dastgiri
- Tabriz Health Services Management Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Asghari Jafarabadi
- Cabrini Research, Cabrini Health, Australia; School of Public Health and Preventative Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia; Road and Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Mashhadi Abdolahi
- Tabriz Health Services Management Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Beltrán-García J, Osca-Verdegal R, Mena-Mollá S, Seco-Cervera M, Peiró-Chova L, García-Giménez JL, Laurent-Puig P, Cervantes A. Translational epigenetics in precision medicine of colorectal cancer. EPIGENETICS IN PRECISION MEDICINE 2022:19-41. [DOI: 10.1016/b978-0-12-823008-4.00018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Ebner DW, Eckmann JD, Burger KN, Mahoney DW, Whitaker TJ, Petersen IA, Kisiel JB. High Positive Predictive Value of Multitarget Stool DNA After Aerodigestive Tract Radiotherapy. GASTRO HEP ADVANCES 2022; 1:746-754. [PMID: 36117548 PMCID: PMC9481191 DOI: 10.1016/j.gastha.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND AND AIMS: Multitarget stool DNA (mt-sDNA) is approved for average-risk colorectal cancer screening; test performance in persons with prior radiation therapy (RT) has not been studied. RT can induce gastrointestinal bleeding and alter DNA methylation, which may affect mt-sDNA accuracy. Among patients previously treated with RT, we aimed to measure the positive predictive value (PPV) of mt-sDNA and compare these results to historical estimates of mt-sDNA PPV among average-risk patients. METHODS: After institutional review board approval, we conducted a retrospective cohort study of a multisite academic and community-based practice. Patients with RT and subsequent mt-sDNA use during the study period (2014–2016) were identified. The findings at diagnostic colonoscopy were compared with published reports among average-risk patients. Nominal P values were generated by 2-tailed Fisher’s exact testing in comparisons of colorectal neoplasia (CRN) rates between groups. RESULTS: There were 220 patients who had RT before mt-sDNA testing. RT was delivered along the aerodigestive tract in 108 patients. Mt-sDNA tests were positive in 45 of 220 patients (20%), and colonoscopy findings were available for 42; 31 of 42 patients (74%) had CRN. PPV by mt-sDNA was similar when stratified by site of prior RT (along vs outside the aerodigestive tract; P = 1.00). Detection of advanced CRN (36%) was nominally higher than previously published retrospective (27%) and prospective (20%) studies. The median time from the start of RT to mt-sDNA use was 7 (interquartile range, 3–14) years. CONCLUSION: With a test positivity rate and PPV for CRN similar to reports among average-risk patients, prior RT does not appear to adversely affect mt-sDNA performance.
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21
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Zou J, Xiao Z, Wu Y, Yang J, Cui N. Noninvasive fecal testing for colorectal cancer. Clin Chim Acta 2021; 524:123-131. [PMID: 34756863 DOI: 10.1016/j.cca.2021.10.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the third most common malignancy worldwide, with the second highest mortality rate among all malignancies. In this review, we describe the current utility of stool diagnostic biomarkers for CRC. METHODS We reviewed stool-related tests and biomarker candidates for the diagnosis of CRC. The guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and multitarget stool DNA test (MT-sDNA) have been used as clinical CRC screening tools. Although microRNAs, protein biomarkers, and microbiota have not yet been used in clinical CRC screening, there is growing evidence that they have the potential to function as CRC screening tools. RESULTS According to the literature, the sensitivity of MT-sDNA for detecting CRC was 87.0-100%, 32.7-82.0% for advanced adenomas, and the specificity was 86.1-95.2%. The sensitivity of individual biomarkers of fecal microRNAs for detecting CRC was 34.2-88.2%, 73.0% for advanced adenomas, and the specificity was 68-100%. The sensitivity of fecal protein markers for detecting CRC was 63.6-93.0%, 47.7-69.4% for advanced adenomas, and the specificity was 38.3-97.5%. The sensitivity of fecal microbiota for detecting CRC was 54.0-100.0%, 32.0-48.3% for advanced adenomas, and the specificity was 61.3-90.0%. CONCLUSION MT-sDNA is the most sensitive CRC screening test, and its sensitivity is the highest for advanced adenomas; however, its detection cost is high. MT-sDNA was more sensitive to CRC and advanced precancerous lesions than FIT, but compared to three years of MT-sDNA, annual FIT as the first non-invasive screening test for CRC seemed to be more effective.
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Affiliation(s)
- Jianhua Zou
- China Academy of Chinese Medical Sciences Xiyuan Hospital, Beijing, China
| | - Zhanshuo Xiao
- China Academy of Chinese Medical Sciences Guanganmen Hospital, Beijing, China
| | - Yu Wu
- China Academy of Chinese Medical Sciences Xiyuan Hospital, Beijing, China.
| | - Jingyan Yang
- China Academy of Chinese Medical Sciences Xiyuan Hospital, Beijing, China
| | - Ning Cui
- China Academy of Chinese Medical Sciences Xiyuan Hospital, Beijing, China
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Validation of a methylated DNA marker panel for the nonendoscopic detection of Barrett's esophagus in a multisite case-control study. Gastrointest Endosc 2021; 94:498-505. [PMID: 33857451 PMCID: PMC8380660 DOI: 10.1016/j.gie.2021.03.937] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/30/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS We previously identified a 5 methylated DNA marker (MDM) panel for the detection of nonendoscopic Barrett's esophagus (BE). In this study, we aimed to recalibrate the performance of the 5 MDM panel using a simplified assay in a training cohort, validate the panel in an independent test cohort, and explore the accuracy of an MDM panel with only 3 markers. METHODS Participants were recruited from 3 medical centers. The sponge on a string device (EsophaCap; CapNostics, Concord, NC, USA) was swallowed and withdrawn, followed by endoscopy, in BE cases and control subjects. A 5 MDM panel was blindly assayed using a simplified assay. Random forest modeling analysis was performed, in silico cross-validated in the training set, and then locked down, before test set analysis. RESULTS The training set had 199 patients: 110 BE cases and 89 control subjects, and the test set had 89 patients: 60 BE cases and 29 control subjects. Sensitivity of the 5 MDM panel for BE diagnosis was 93% at 90% specificity in the training set and 93% at 93% specificity in the test set. Areas under the receiver operating characteristic curves were .96 and .97 in the training and test sets, respectively. Model accuracy was not influenced by age, sex, or smoking history. Multiple 3 MDM panels achieved similar accuracy. CONCLUSIONS A 5 MDM panel for BE is highly accurate in training and test sets in a blinded multisite case-control analysis using a simplified assay. This panel may be reduced to only 3 MDMs in the future. (Clinical trial registration number: NCT02560623.).
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23
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Yang JD, Ghoz H, Aboelsoud MM, Taylor WR, Yab TC, Berger CK, Cao X, Foote PH, Giama NH, Barr Fritcher EG, Mahoney DW, Moser CD, Smyrk TC, Kipp BR, Gores GJ, Roberts LR, Kisiel JB. DNA Methylation Markers for Detection of Cholangiocarcinoma: Discovery, Validation, and Clinical Testing in Biliary Brushings and Plasma. Hepatol Commun 2021; 5:1448-1459. [PMID: 34430788 PMCID: PMC8369938 DOI: 10.1002/hep4.1730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/03/2021] [Accepted: 03/22/2021] [Indexed: 02/04/2023] Open
Abstract
Cholangiocarcinoma (CCA) has poor prognosis due to late-stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced-representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin-fixed, paraffin-embedded CCA tumors and adjacent hepatobiliary control tissues using methylation-specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95-1.0). In the clinical pilot on plasma, a cross-validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81-0.95]) but not for primary sclerosing cholangitis-associated eCCA (AUC, 0.54 [0.35-0.73]). Conclusion: Next-generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and HepatologyCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Hassan Ghoz
- Division of Gastroenterology and HepatologyMayo ClinicJacksonvilleFLUSA
| | | | - William R. Taylor
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Tracy C. Yab
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Calise K. Berger
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Xiaoming Cao
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Patrick H. Foote
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Nasra H. Giama
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | | | - Douglas W. Mahoney
- Department of Biomedical Statistics and InformaticsMayo ClinicRochesterMNUSA
| | - Catherine D. Moser
- Department of Pathology and Laboratory MedicineChildren’s Healthcare of AtlantaAtlantaGAUSA
| | | | | | - Gregory J. Gores
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Lewis R. Roberts
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - John B. Kisiel
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
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Ebner DW, Eckmann JD, Burger KN, Mahoney DW, Bering J, Kahn A, Rodriguez EA, Prichard DO, Wallace MB, Kane SV, Finney Rutten LJ, Gurudu SR, Kisiel JB. Detection of Postcolonoscopy Colorectal Neoplasia by Multi-target Stool DNA. Clin Transl Gastroenterol 2021; 12:e00375. [PMID: 34140458 PMCID: PMC8216679 DOI: 10.14309/ctg.0000000000000375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/20/2021] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Significant variability between colonoscopy operators contributes to postcolonoscopy colorectal cancers (CRCs). We aimed to estimate postcolonoscopy colorectal neoplasia (CRN) detection by multi-target stool DNA (mt-sDNA), which has not previously been studied for this purpose. METHODS In a retrospective cohort of patients with +mt-sDNA and completed follow-up colonoscopy, positive predictive value (PPV) for endpoints of any CRN, advanced adenoma, right-sided neoplasia, sessile serrated polyps (SSP), and CRC were stratified by the time since previous colonoscopy (0-9, 10, and ≥11 years). mt-sDNA PPV at ≤9 years from previous average-risk screening colonoscopy was used to estimate CRN missed at previous screening colonoscopy. RESULTS Among the 850 studied patients with +mt-sDNA after a previous negative screening colonoscopy, any CRN was found in 535 (PPV 63%). Among 107 average-risk patients having +mt-sDNA ≤9 years after last negative colonoscopy, any CRN was found in 67 (PPV 63%), advanced neoplasia in 16 (PPV 15%), right-sided CRN in 48 (PPV 46%), and SSP in 20 (PPV 19%). These rates were similar to those in 47 additional average risk persons with previous incomplete colonoscopy and in an additional 68 persons at increased CRC risk. One CRC (stage I) was found in an average risk patient who was mt-sDNA positive 6 years after negative screening colonoscopy. DISCUSSION The high PPV of mt-sDNA 0-9 years after a negative screening colonoscopy suggests that lesions were likely missed on previous examination or may have arisen de novo. mt-sDNA as an interval test after negative screening colonoscopy warrants further study.
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Affiliation(s)
- Derek W. Ebner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jason D. Eckmann
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kelli N. Burger
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Douglas W. Mahoney
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Jamie Bering
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Allon Kahn
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Eduardo A. Rodriguez
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - David O. Prichard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic Health System, La Crosse, Wisconsin, USA
| | - Michael B. Wallace
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Sunanda V. Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Suryakanth R. Gurudu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - John B. Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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25
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Barnell EK, Kang Y, Barnell AR, Kruse KR, Fiske J, Pittz ZR, Khan AR, Huebner TA, Holmes FL, Griffith M, Griffith OL, Chaudhuri AA, Wurtzler EM. Multitarget Stool RNA Test for Noninvasive Detection of Colorectal Neoplasias in a Multicenter, Prospective, and Retrospective Cohort. Clin Transl Gastroenterol 2021; 12:e00360. [PMID: 34029233 PMCID: PMC8148418 DOI: 10.14309/ctg.0000000000000360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Effective colorectal cancer (CRC) prevention and screening requires sensitive detection of all advanced neoplasias (CRC and advanced adenomas [AA]). However, existing noninvasive screening approaches cannot accurately detect adenomas with high sensitivity. METHODS Here, we describe a multifactor assay (RNA-FIT test) that combines 8 stool-derived eukaryotic RNA biomarkers, patient demographic information (smoking status), and a fecal immunochemical test (FIT) to sensitively detect advanced colorectal neoplasias and other non-advanced adenomas in a 1,305-patient, average-risk, prospective cohort. This cohort was supplemented with a 22-patient retrospective cohort consisting of stool samples obtained from patients diagnosed with AA or CRC before treatment or resection. Participants within these cohorts were evaluated with the RNA-FIT assay and an optical colonoscopy. RNA-FIT test results were compared with colonoscopy findings. RESULTS Model performance was assessed through 5-fold internal cross-validation of the training set (n = 939) and by using the model on a hold out testing set (n = 388). When used on the hold out testing set, the RNA-FIT test attained a 95% sensitivity for CRC (n = 22), 62% sensitivity for AA (n = 52), 25% sensitivity for other non-AA (n = 139), 80% specificity for hyperplastic polyps (n = 74), and 85% specificity for no findings on a colonoscopy (n = 101). DISCUSSION The RNA-FIT assay demonstrated clinically relevant detection of all grades of colorectal neoplasia, including carcinomas, AAs, and ONAs. This assay could represent a noninvasive option to screen for both CRC and precancerous adenomas.
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Affiliation(s)
- Erica K. Barnell
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Yiming Kang
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
| | - Andrew R. Barnell
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
| | - Kimberly R. Kruse
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
| | - Jared Fiske
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
| | - Zachary R. Pittz
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
| | - Adnan R. Khan
- Department of Pathology, Integrated Cellular and Molecular Diagnostics, Greenbelt, Maryland, USA
- Elligo Health Research, Austin, Texas, USA
| | - Thomas A. Huebner
- Elligo Health Research, Austin, Texas, USA
- Department of Pathology, Division of Gastrointestinal and Liver Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | | | - Malachi Griffith
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Obi L. Griffith
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Aadel A. Chaudhuri
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Elizabeth M. Wurtzler
- Division of Gastroenterology and Hepatology, Geneoscopy Inc., St. Louis, Missouri, USA
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26
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Grady WM. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Adv Cancer Res 2021; 151:425-468. [PMID: 34148620 DOI: 10.1016/bs.acr.2021.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer related deaths worldwide. One of the hallmarks of cancer and a fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological process of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the initiation and progression of cancers, including colorectal cancer. Epigenetic alterations, which include changes affecting DNA methylation, histone modifications, chromatin structure, and noncoding RNA expression, have emerged as a major class of molecular alteration in colon polyps and colorectal cancer. The classes of epigenetic alterations, their status in colorectal polyps and cancer, their effects on neoplasm biology, and their application to clinical care will be discussed.
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Affiliation(s)
- William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, United States.
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27
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Majumder S, Taylor WR, Foote PH, Berger CK, Wu CW, Mahoney DW, Bamlet WR, Burger KN, Postier N, de la Fuente J, Doering KA, Lidgard GP, Allawi HT, Petersen GM, Chari ST, Ahlquist DA, Kisiel JB. High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9. Clin Cancer Res 2021; 27:2523-2532. [PMID: 33593879 DOI: 10.1158/1078-0432.ccr-20-0235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 09/03/2020] [Accepted: 02/11/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case-control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC. EXPERIMENTAL DESIGN Thirteen MDMs (GRIN2D, CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated. RESULTS The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86-0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%. CONCLUSIONS Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.
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Affiliation(s)
- Shounak Majumder
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - William R Taylor
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick H Foote
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Calise K Berger
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Chung Wah Wu
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Douglas W Mahoney
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - William R Bamlet
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Kelli N Burger
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Neil Postier
- Department of Chemistry, Wheaton College, Wheaton, Illinois
| | - Jaime de la Fuente
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Karen A Doering
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Suresh T Chari
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - David A Ahlquist
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John B Kisiel
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
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28
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Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
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Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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Wang DY, He KX, Huang Y, Lou QQ, He T, Xu X. A New Method for the Detection of Colorectal Cancer and the Precancerous Lesions: Occult Blood Testing Combination with Promoter Methylation in the Fecal Sample. J Cancer 2021; 12:335-342. [PMID: 33391430 PMCID: PMC7738999 DOI: 10.7150/jca.50525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/24/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Noninvasive stool-based DNA methylation testing emerges as a new approach for detecting colorectal cancer (CRC). However, its feasibility for early detection of CRC and precancerous lesions in the Chinese population remains inconclusive. Methods: In this study, we establish a possibilities screening method (sDNA-FOBT) for detecting CRC and precancerous lesions (hyperplastic polyps [HP] and adenomas [AD]) and evaluate its detection performance in the Chinese population. This method combined a molecular assay of DNA methylation markers (BMP3, NDRG4, and SDC2) with the human hemoglobin test (FOBT) in stool samples. Results: The sensitivity of sDNA-FOBT was 85.42% for CRC, 85.71% for AD, and 28.21% for HP, respectively, at the specificity of 92%. The diagnostic efficacy of sDNA-FOBT for detecting CRC and precancerous lesions was significantly higher than FOBT alone (sensitivity: 61.70% vs. 51.06%, P<0.01; AUC: 0.78 vs. 0.72, P<0.001), especially for CRC (AUC: 0.91 vs. 0.86, P<0.001) and AD (AUC: 0.91 vs. 0.75, P<0.05). No significant difference was observed between the detection sensitivity of sDNA-FOBT and the clinical variables. Notably, compared with FOBT, sDNA-FOBT was more effective in the detection of CRC and precancerous lesions in the patients aged >50 y (62.34% vs 54.55%, P<0.05). Conclusion: Our results demonstrate that sDNA-FOBT is a promising method for screening CRC and precancerous lesions in the Chinese population. Further studies are required to validate the results in a larger sample capacity.
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Affiliation(s)
- Dan-Yang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kang-Xin He
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Huang
- Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qin-Qin Lou
- Hangzhou Youke Biomedical Inc., Hangzhou, China
| | - Ti He
- Shanghai Genechem Clinical Laboratory Inc., Shanghai, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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30
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Ballester V, Taylor WR, Slettedahl SW, Mahoney DW, Yab TC, Sinicrope FA, Boland CR, Lidgard GP, Cruz-Correa MR, Smyrk TC, Boardman LA, Ahlquist DA, Kisiel JB. Novel methylated DNA markers accurately discriminate Lynch syndrome associated colorectal neoplasia. Epigenomics 2020; 12:2173-2187. [PMID: 33350853 PMCID: PMC7923255 DOI: 10.2217/epi-2020-0132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients. Patients & methods: For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls. Results: OPLAH was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. ALKBH5, was uniquely hypermethylated in LS neoplasms. Conclusion: Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.
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Affiliation(s)
- Veroushka Ballester
- Division of Digestive & Liver Diseases, Columbia University, New York, NY 10032, USA
| | - William R Taylor
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - Tracy C Yab
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Frank A Sinicrope
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - Marcia R Cruz-Correa
- Comprehensive Cancer Center, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA
| | - Thomas C Smyrk
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | - Lisa A Boardman
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - David A Ahlquist
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - John B Kisiel
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
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31
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Affiliation(s)
- John B. Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester Minnesota, USA
| | - Paul J. Limburg
- Division of Gastroenterology and Hepatology, Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester Minnesota, USA
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32
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Limburg PJ, Mahoney DW, Ahlquist DA, Allawi HT, Johnson SC, Kaiser M, Katerov VE, Statz S, Graham RP, Foote PH, Doering KA, Burger KN, Lidgard GP, Kisiel JB. Comparison of Tissue-Based Molecular Markers in Younger versus Older Patients with Colorectal Neoplasia. Cancer Epidemiol Biomarkers Prev 2020; 29:1570-1576. [PMID: 32467348 PMCID: PMC10964290 DOI: 10.1158/1055-9965.epi-19-1598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/12/2020] [Accepted: 05/22/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Emerging colorectal cancer trends demonstrate increased incidence and mortality in younger populations, prompting consideration of average-risk colorectal cancer screening initiation at age 45 versus 50 years. However, screening test performance characteristics in adults 45-49 years have been minimally described. To inform the biologic rationale for multi-target stool DNA (mt-sDNA) screening in younger patients, we analyzed and compared tissue levels of methylation (BMP3, NDRG4) and mutation (KRAS) markers included in the FDA-approved, mt-sDNA assay (Cologuard; Exact Sciences Corporation). METHODS Within 40-44, 45-49, and 50-64 year age groups, archived colorectal tissue specimens were identified for 211 sporadic colorectal cancer cases, 123 advanced precancerous lesions (APLs; adenomas >1 cm, high-grade dysplasia, ≥25% villous morphology, or sessile serrated polyp; 45-49 and 50-64 age groups only), and 204 histologically normal controls. Following DNA extraction, KRAS, BMP3, and NDRG4 were quantified using QuARTS assays, relative to ACTB (reference gene). RESULTS None of the molecular marker concentrations were significantly associated with age (P > 0.05 for all comparisons), with the exception of NDRG4 concentration in APL samples (higher in older vs. younger cases; P = 0.008). However, NDRG4 levels were also statistically higher in APL case versus normal control samples in both the 45-49 (P < 0.0001) and 50-64 (P < 0.0001) year age groups. CONCLUSIONS Overall, these findings support the potential for earlier onset of average-risk colorectal cancer screening with the mt-sDNA assay. IMPACT These novel data address an identified knowledge gap and strengthen the biologic basis for earlier-onset, average-risk screening with the mt-sDNA assay.
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Affiliation(s)
- Paul J Limburg
- Department of Medicine, Mayo Clinic, Rochester, Minnesota.
| | - Douglas W Mahoney
- Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota
| | | | | | | | | | | | | | - Rondell P Graham
- Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Kelli N Burger
- Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota
| | | | - John B Kisiel
- Department of Medicine, Mayo Clinic, Rochester, Minnesota
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Current status of development of methylation biomarkers for in vitro diagnostic IVD applications. Clin Epigenetics 2020; 12:100. [PMID: 32631437 PMCID: PMC7336678 DOI: 10.1186/s13148-020-00886-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
A significant volume of research clearly shows that disease-related methylation changes can be used as biomarkers at all stages of clinical disease management, including risk assessment and predisposition screening through early diagnostics to personalization of patient care and monitoring of the relapse and chronic disease. Thus disease-related methylation changes are an attractive source of the biomarkers that can have significant impact on precision medicine. However, the translation of the research findings in methylation biomarkers field to clinical practice is at the very least not satisfactory. That is mainly because the evidence generated in research studies indicating the utility of the disease-related methylation change to predict clinical outcome is in majority of the cases not sufficient to postulate the diagnostic use of the biomarker. The research studies need to be followed by well-designed and systematic investigations of clinical utility of the biomarker that produce data of sufficient quality to meet regulatory approval for the test to be used to make clinically valid decision. In this review, we describe methylation-based IVD tests currently approved for IVD use or at the advanced stages of the development for the diagnostic use. For each of those tests, we analyze the technologies that the test utilizes for methylation detection as well as describe the types of the clinical studies that were performed to show clinical validity of the test and warrant regulatory approval. The examples reviewed here should help with planning of clinical investigations and delivery of the clinical evidence required for the regulatory approval of potential methylation biomarker based IVD tests.
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Loktionov A, Soubieres A, Bandaletova T, Francis N, Allison J, Sturt J, Mathur J, Poullis A. Biomarker measurement in non-invasively sampled colorectal mucus as a novel approach to colorectal cancer detection: screening and triage implications. Br J Cancer 2020; 123:252-260. [PMID: 32398859 PMCID: PMC7374197 DOI: 10.1038/s41416-020-0893-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/11/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Faecal tests are widely applied for colorectal cancer (CRC) screening and considered for triaging symptomatic patients with suspected CRC. However, faecal tests can be inconvenient, complex and expensive. Colorectal mucus (CM) sampled using our new patient-friendly non-invasive technique is rich in CRC biomarkers. This study aimed to evaluate diagnostic accuracy of CRC detection by measuring protein biomarkers in CM. METHODS Colorectal mucus samples were provided by 35 healthy controls, 62 CRC-free symptomatic patients and 40 CRC patients. Biomarkers were quantified by ELISA. Diagnostic performances of haemoglobin, C-reactive protein, tissue inhibitor of metalloproteinases-1, M2-pyruvate kinase, matrix metalloproteinase-9, peptidyl arginine deiminase-4, epidermal growth factor receptor, calprotectin and eosinophil-derived neurotoxin were assessed using receiver operating characteristic (ROC) curve analysis. RESULTS Colorectal mucus haemoglobin was superior compared to other biomarkers. For haemoglobin, the areas under the curve for discriminating between CRC and healthy groups ('screening') and between CRC and symptomatic patients ('triage') were 0.921 and 0.854 respectively. The sensitivity of 80.0% and specificities of 94.3% and 85.5% for the two settings respectively were obtained. CONCLUSIONS Haemoglobin quantification in CM reliably detects CRC. This patient-friendly approach presents an attractive alternative to faecal immunochemical test; however, the two methods need to be directly compared in larger studies.
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Affiliation(s)
- Alexandre Loktionov
- DiagNodus Ltd, Babraham Research Campus, Cambridge, UK.
- DiagNodus Ltd, St John's Innovation Centre, Cowley Road, Cambridge, UK.
| | - Anet Soubieres
- Department of Gastroenterology, St George's Hospital, London, UK
- Department of Gastroenterology, Charing Cross Hospital, London, UK
| | - Tatiana Bandaletova
- DiagNodus Ltd, Babraham Research Campus, Cambridge, UK
- DiagNodus Ltd, St John's Innovation Centre, Cowley Road, Cambridge, UK
| | - Nader Francis
- Department of Surgery, Yeovil District Hospital, Yeovil, UK
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Joanna Allison
- Department of Surgery, Yeovil District Hospital, Yeovil, UK
| | - Julian Sturt
- Department of Surgery, Southend University Hospital, Southend-on-Sea, UK
| | - Jai Mathur
- Department of Gastroenterology, St George's Hospital, London, UK
| | - Andrew Poullis
- Department of Gastroenterology, St George's Hospital, London, UK
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Kisiel JB, Eckmann JD, Limburg PJ. Multitarget Stool DNA for Average Risk Colorectal Cancer Screening: Major Achievements and Future Directions. Gastrointest Endosc Clin N Am 2020; 30:553-568. [PMID: 32439088 PMCID: PMC10964930 DOI: 10.1016/j.giec.2020.02.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
After 2 screen-setting studies showing high sensitivity for colorectal cancer and advanced precancerous lesions, multitarget stool DNA testing was endorsed by the US Preventative Services Task Force as a first-line colorectal cancer screening test. Uptake has increased exponentially since approval by the US Food and Drug Administration and Centers for Medicare and Medicaid Services. Adherence to testing is approximately 70%. Patients with positive results have high diagnostic colonoscopy completion rates in single-center studies. The positive predictive value for colorectal neoplasia in postapproval studies is high. Next-generation test prototypes show promise to extend specificity gains while maintaining high sensitivity.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA.
| | - Jason D Eckmann
- Department of Internal Medicine, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA. https://twitter.com/JasonEckmannMD
| | - Paul J Limburg
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, Southwest, Rochester, MN 55905, USA. https://twitter.com/limburg_paul
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Ebner DW, Kisiel JB. Stool-Based Tests for Colorectal Cancer Screening: Performance Benchmarks Lead to High Expected Efficacy. Curr Gastroenterol Rep 2020; 22:32. [PMID: 32494878 PMCID: PMC7271040 DOI: 10.1007/s11894-020-00770-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Participation goals for colorectal cancer (CRC) screening in the USA have not been met. Non-invasive screening strategies may improve CRC screening participation. We highlight recent literature on stool-based screening performance and expectations for emerging non-invasive screening tests. RECENT FINDINGS Stool-based CRC screening detects screen-relevant colorectal neoplasia and outperforms a currently available plasma assay. Though modestly sensitive for CRC, adherence to annual fecal immunochemical testing (FIT) is sub-optimal. Multi-target stool DNA (MT-sDNA) has greater adherence, superior sensitivity for screen-relevant lesions (including those in the proximal colon and sessile serrated architecture), and equivalent specificity to FIT over a 3-year period. Stool-based CRC screening tests are anticipated to reduce the incidence and mortality of CRC through detection of early-stage cancers and high-risk polyps. These endpoints in performance will need to be met by emerging blood sample-based tests in order have meaningful impact in clinical practice.
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Affiliation(s)
- Derek W Ebner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Siskova A, Cervena K, Kral J, Hucl T, Vodicka P, Vymetalkova V. Colorectal Adenomas-Genetics and Searching for New Molecular Screening Biomarkers. Int J Mol Sci 2020; 21:ijms21093260. [PMID: 32380676 PMCID: PMC7247353 DOI: 10.3390/ijms21093260] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/01/2020] [Accepted: 05/02/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a malignant disease with an incidence of over 1.8 million new cases per year worldwide. CRC outcome is closely related to the respective stage of CRC and is more favorable at less advanced stages. Detection of early colorectal adenomas is the key to survival. In spite of implemented screening programs showing efficiency in the detection of early precancerous lesions and CRC in asymptomatic patients, a significant number of patients are still diagnosed in advanced stages. Research on CRC accomplished during the last decade has improved our understanding of the etiology and development of colorectal adenomas and revealed weaknesses in the general approach to their detection and elimination. Recent studies seek to find a reliable non-invasive biomarker detectable even in the blood. New candidate biomarkers could be selected on the basis of so-called liquid biopsy, such as long non-coding RNA, microRNA, circulating cell-free DNA, circulating tumor cells, and inflammatory factors released from the adenoma into circulation. In this work, we focused on both genetic and epigenetic changes associated with the development of colorectal adenomas into colorectal carcinoma and we also discuss new possible biomarkers that are detectable even in adenomas prior to cancer development.
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Affiliation(s)
- Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Correspondence: (A.S.); (P.V.); Tel.: +420-241062251 (A.S.); +420-241062694 (P.V.)
| | - Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
| | - Jan Kral
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic;
| | - Tomas Hucl
- Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic;
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 32300 Pilsen, Czech Republic
- Correspondence: (A.S.); (P.V.); Tel.: +420-241062251 (A.S.); +420-241062694 (P.V.)
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 32300 Pilsen, Czech Republic
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Berger BM, Kisiel JB, Imperiale TF, Geenen DJ, Heigh RI, Mahoney DW, Hilsden RJ. Low Incidence of Aerodigestive Cancers in Patients With Negative Results From Colonoscopies, Regardless of Findings From Multitarget Stool DNA Tests. Clin Gastroenterol Hepatol 2020; 18:864-871. [PMID: 31394289 PMCID: PMC10964931 DOI: 10.1016/j.cgh.2019.07.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/11/2019] [Accepted: 07/28/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence. METHODS We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test. Outcomes included aerodigestive cancers in discordant vs concordant groups and comparison of observed aerodigestive cancer incidence between the groups and compared with expected incidence for the population, based on the Surveillance, Epidemiology, and End Results (SEER) data. RESULTS Median follow-up times were comparable between subjects in the discordant (5.3 y; interquartile range, 3.5-5.8 y) and concordant (5.4 y; interquartile range, 3.7-5.8 y) groups. Aerodigestive cancers developed in 5 subjects in the discordant group vs 11 subjects in the concordant group (crude risk ratio, 2.3; 95% CI, 0.8-6.6; adjusted risk ratio, 2.2; 95% CI, 0.8-6.2; P = .151). The incidence of aerodigestive cancer was lower in the concordant group than the expected incidence based on SEER data (risk ratio, 0.4; 95% CI, 0.2-0.6; P = .0008). The incidence of aerodigestive cancer was not significantly greater in the population in the discordant group than the expected incidence based on SEER data (risk ratio, 0.8; 95% CI, 0.3-1.9; P = .599). CONCLUSIONS In a retrospective study with a median follow-up time of 5.4 years, incident aerodigestive cancers were uncommon among subjects with negative findings from colonoscopies, regardless of discordant or concordant results from multitarget stool DNA tests. Patients with negative results from high-quality colonoscopies therefore should not undergo further testing.
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Affiliation(s)
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Thomas F Imperiale
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Daniel J Geenen
- Wisconsin Center for Advanced Research, Milwaukee, Wisconsin
| | - Russell I Heigh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Douglas W Mahoney
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Robert J Hilsden
- Departments of Medicine/Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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Multitarget Stool DNA Screening in Clinical Practice: High Positive Predictive Value for Colorectal Neoplasia Regardless of Exposure to Previous Colonoscopy. Am J Gastroenterol 2020; 115:608-615. [PMID: 32068535 PMCID: PMC7127971 DOI: 10.14309/ajg.0000000000000546] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.
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Robertson DJ, Dominitz JA. When Results From Multitarget DNA Tests Are Positive and Colonoscopy Is Negative, Should We Be Concerned About Cancer Outside the Colon? Clin Gastroenterol Hepatol 2020; 18:783-786. [PMID: 31626977 DOI: 10.1016/j.cgh.2019.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Affiliation(s)
- Douglas J Robertson
- Department of Veterans Affairs Medical Center, White River Junction, Vermont; The Geisel School of Medicine at Dartmouth, The Dartmouth Institute, Hanover, New Hampshire
| | - Jason A Dominitz
- VA Puget Sound Health Care System, University of Washington School of Medicine, Seattle, Washington
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Eckmann JD, Ebner DW, Kisiel JB. Multi-Target Stool DNA Testing for Colorectal Cancer Screening: Emerging Learning on Real-world Performance. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2020; 18:109-119. [PMID: 31965446 PMCID: PMC10966619 DOI: 10.1007/s11938-020-00271-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Multi-target stool DNA (MT-sDNA) was approved in 2014 for use in screening average-risk patients for colorectal cancer (CRC). Here, we highlight recent literature from post-market studies to provide an update on clinical use and utility not possible from pre-approval studies. RECENT FINDINGS MT-sDNA has been included in major society guidelines as an option for colorectal cancer screening, and has seen exponentially increasing use in clinical practice. MT-sDNA appears to be attracting new patients to CRC screening, and patient adherence to diagnostic colonoscopy after a positive MT-sDNA test is high. Approximately two-thirds of these patients are found to have colorectal neoplasia (CRN), 80% of whom have at least one right-sided lesion; 1 in 3 will have advanced CRN. High yield of CRN is due not only to post-screening increase in probability but also likely improved endoscopist attention. In those with a negative high-quality colonoscopy after positive MT-sDNA test ("false positive MT-sDNA"), further interventions do not appear to be necessary. SUMMARY MT-sDNA is a promising tool to improve rates and quality of CRC screening. Further investigation should examine MT-sDNA performance in populations at increased risk for CRC, and as an interval test after colonoscopy to detect potentially missed lesions.
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Affiliation(s)
- Jason D Eckmann
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Derek W Ebner
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA.
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Loktionov A. Biomarkers for detecting colorectal cancer non-invasively: DNA, RNA or proteins? World J Gastrointest Oncol 2020; 12:124-148. [PMID: 32104546 PMCID: PMC7031146 DOI: 10.4251/wjgo.v12.i2.124] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/30/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a global problem affecting millions of people worldwide. This disease is unique because of its slow progress that makes it preventable and often curable. CRC symptoms usually emerge only at advanced stages of the disease, consequently its early detection can be achieved only through active population screening, which markedly reduces mortality due to this cancer. CRC screening tests that employ non-invasively detectable biomarkers are currently being actively developed and, in most cases, samples of either stool or blood are used. However, alternative biological substances that can be collected non-invasively (colorectal mucus, urine, saliva, exhaled air) have now emerged as new sources of diagnostic biomarkers. The main categories of currently explored CRC biomarkers are: (1) Proteins (comprising widely used haemoglobin); (2) DNA (including mutations and methylation markers); (3) RNA (in particular microRNAs); (4) Low molecular weight metabolites (comprising volatile organic compounds) detectable by metabolomic techniques; and (5) Shifts in gut microbiome composition. Numerous tests for early CRC detection employing such non-invasive biomarkers have been proposed and clinically studied. While some of these studies generated promising early results, very few of the proposed tests have been transformed into clinically validated diagnostic/screening techniques. Such DNA-based tests as Food and Drug Administration-approved multitarget stool test (marketed as Cologuard®) or blood test for methylated septin 9 (marketed as Epi proColon® 2.0 CE) show good diagnostic performance but remain too expensive and technically complex to become effective CRC screening tools. It can be concluded that, despite its deficiencies, the protein (haemoglobin) detection-based faecal immunochemical test (FIT) today presents the most cost-effective option for non-invasive CRC screening. The combination of non-invasive FIT and confirmatory invasive colonoscopy is the current strategy of choice for CRC screening. However, continuing intense research in the area promises the emergence of new superior non-invasive CRC screening tests that will allow the development of improved disease prevention strategies.
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Weiser E, Parks PD, Swartz RK, Thomme JV, Lavin PT, Limburg P, Berger BM. Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening: Real-world data from a large cohort of older adults. J Med Screen 2020; 28:18-24. [PMID: 32054393 PMCID: PMC7905742 DOI: 10.1177/0969141320903756] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Objective To determine cross-sectional adherence with the multi-target stool DNA test used for colorectal cancer screening in a large, fully insured Medicare population. Methods All patients aged 65–85 with a valid multi-target stool DNA test order from 1 September 2016 to 31 August 2017 identified from the Exact Sciences Laboratories (Madison, WI; sole-source national multi-target stool DNA test provider) database were evaluated for test adherence. Cross-sectional adherence, defined as multi-target stool DNA test completion within 365 days from order date, was analyzed overall and by time to adherence, as well as by available patient (age, sex, test order date, Medicare coverage type) and provider (specialty, year of first multi-target stool DNA test order, multi-target stool DNA test order frequency, and practice location) factors. Results Among 368,494 Medicare beneficiaries (64% female), overall cross-sectional adherence was 71%. Cumulative adherence rates increased more rapidly at 30 (44%) and 60 (65%) days, followed by more gradual increases at 90 (67%), 180 (70%), and 365 (71%) days. By provider specialty, primary care clinicians represented a higher percentage of multi-target stool DNA orders than gastroenterologists (88% vs. 6%), but had a lower associated patient adherence rate (71% vs. 78%). Conclusions In this large, national sample of Medicare insured older adults, nearly three-quarters of patients adhered with a multi-target stool DNA order for colorectal cancer screening. These real-world data should inform further clinical and population health applications, reimbursement model simulations, and guideline-endorsed colorectal cancer screening strategies adherence.
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Affiliation(s)
| | | | | | | | - Philip T Lavin
- Boston Biostatistics Research Foundation, Framingham, USA
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Barnell EK, Kang Y, Wurtzler EM, Griffith M, Chaudhuri AA, Griffith OL. Reply. Gastroenterology 2020; 158:793-794. [PMID: 31743736 DOI: 10.1053/j.gastro.2019.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 12/02/2022]
Affiliation(s)
- Erica K Barnell
- McDonnell Genome Institute, Washington University School of Medicine, and Geneoscopy, LLC, Division of Gastroenterology and Hepatology, St. Louis, Missouri
| | - Yiming Kang
- Geneoscopy, LLC, Division of Gastroenterology and Hepatology, and Department of Computer Science and Engineering, Washington University, St. Louis, Missouri
| | - Elizabeth M Wurtzler
- Geneoscopy, LLC, Division of Gastroenterology and Hepatology, St. Louis, Missouri
| | - Malachi Griffith
- McDonnell Genome Institute, and Department of Genetics, and Division of Oncology, Department of Medicine, and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - Aadel A Chaudhuri
- Department of Radiation Oncology, and Department of Genetics, and Department of Computer Science and Engineering, and Siteman Cancer Center, and Washington University School of Medicine, St. Louis, Missouri
| | - Obi L Griffith
- McDonnell Genome Institute, and Department of Genetics, and Division of Oncology, Department of Medicine, and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
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Kaminski MF, Robertson DJ, Senore C, Rex DK. Optimizing the Quality of Colorectal Cancer Screening Worldwide. Gastroenterology 2020; 158:404-417. [PMID: 31759062 DOI: 10.1053/j.gastro.2019.11.026] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/04/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022]
Abstract
Screening, followed by colonoscopic polypectomy (or surgery for malignant lesions), prevents incident colorectal cancer and mortality. However, there are variations in effective application of nearly every aspect of the screening process. Screening is a multistep process, and failure in any single step could result in unnecessary morbidity and mortality. Awareness of variations in operator- and system-dependent performance has led to detailed, comprehensive recommendations in the United States and Europe on how colonoscopy screening should be performed and measured. Likewise, guidance has been provided on quality assurance for nonprimary colonoscopy-based screening programs, including strategies to maximize adherence. Quality improvement is now a validated science, and there is clear evidence that higher quality prevents incident cancer and cancer death. Quality must be addressed at the levels of the system, provider, and individuals, to maximize the benefits of screening for any population. We review the important aspects of measuring and improving the quality of colorectal cancer screening.
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Affiliation(s)
- Michael F Kaminski
- Department of Gastroenterological Oncology, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland; Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Douglas J Robertson
- Department of Veterans Affairs Medical Center, White River Junction, Vermont; The Geisel School of Medicine at Dartmouth and The Dartmouth Institute, Hanover, New Hampshire
| | - Carlo Senore
- Epidemiology and Screening Unit-CPO, University Hospital Città della Salute e della Scienza, Turin, Italy
| | - Douglas K Rex
- Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
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46
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Zhan YX, Luo GH. DNA methylation detection methods used in colorectal cancer. World J Clin Cases 2019; 7:2916-2929. [PMID: 31624740 PMCID: PMC6795732 DOI: 10.12998/wjcc.v7.i19.2916] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 08/22/2019] [Accepted: 09/09/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) remains a major contributor to the number of cancer-related deaths that occur annually worldwide. With the development of molecular biology methods, an increasing number of molecular biomarkers have been identified and investigated. CRC is believed to result from an accumulation of epigenetic changes, and detecting aberrant DNA methylation patterns is useful for both the early diagnosis and prognosis of CRC. Numerous studies are focusing on the development of DNA methylation detection methods or DNA methylation panels. Thus, this review will discuss the commonly used techniques and technologies to evaluate DNA methylation, their merits and deficiencies as well as the prospects for new methods.
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Affiliation(s)
- Yu-Xia Zhan
- Comprehensive Laboratory, Changzhou Key Lab of Individualized Diagnosis and Treatment Associated with High Technology Research, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
| | - Guang-Hua Luo
- Comprehensive Laboratory, Changzhou Key Lab of Individualized Diagnosis and Treatment Associated with High Technology Research, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
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47
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Crockett SD, Nagtegaal ID. Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia. Gastroenterology 2019; 157:949-966.e4. [PMID: 31323292 DOI: 10.1053/j.gastro.2019.06.041] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 06/07/2019] [Accepted: 06/15/2019] [Indexed: 12/11/2022]
Abstract
In addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%-40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval-especially in light of concerns regarding incomplete detection and resection.
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Affiliation(s)
- Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
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48
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Natale F, Vivo M, Falco G, Angrisano T. Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis. Clin Epigenetics 2019; 11:132. [PMID: 31492175 PMCID: PMC6729090 DOI: 10.1186/s13148-019-0728-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic pancreatitis presents a high risk of inflammation-related progression to pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The high mortality rate is directly related to the difficulty in promptly diagnosing the disease, which often presents as overt and advanced. Hence, early diagnosis for pancreatic cancer becomes crucial, propelling research into the molecular and epigenetic landscape of the disease. MAIN BODY Recent studies have shown that cell-free DNA methylation profiles from inflammatory diseases or cancer can vary, thus opening a new venue for the development of biomarkers for early diagnosis. In particular, cell-free DNA methylation could be employed in the identification of pre-neoplastic signatures in individuals with suspected pancreatic conditions, representing a specific and non-invasive method of early diagnosis of pancreatic cancer. In this review, we describe the molecular determinants of pancreatic cancer and how these are related to chronic pancreatitis. We will then present an overview of differential methylated genes in the two conditions, highlighting their diagnostic or prognostic potential. CONCLUSION Exploiting the relation between abnormally methylated cell-free DNA and pre-neoplastic lesions or chronic pancreatitis may become a game-changing approach for the development of tools for the early diagnosis of pancreatic cancer.
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Affiliation(s)
- Francesco Natale
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
| | - Maria Vivo
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.,Biogem Scarl, Istituto di Ricerche Genetiche "Gaetano Salvatore", 83031, Ariano Irpino, Italy
| | - Tiziana Angrisano
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
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Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing. Am J Gastroenterol 2019; 114:1539-1549. [PMID: 31306149 PMCID: PMC7294458 DOI: 10.14309/ajg.0000000000000284] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2). DISCUSSION Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
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Beltrán-García J, Osca-Verdegal R, Mena-Mollá S, García-Giménez JL. Epigenetic IVD Tests for Personalized Precision Medicine in Cancer. Front Genet 2019; 10:621. [PMID: 31316555 PMCID: PMC6611494 DOI: 10.3389/fgene.2019.00621] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/13/2019] [Indexed: 12/12/2022] Open
Abstract
Epigenetic alterations play a key role in the initiation and progression of cancer. Therefore, it is possible to use epigenetic marks as biomarkers for predictive and precision medicine in cancer. Precision medicine is poised to impact clinical practice, patients, and healthcare systems. The objective of this review is to provide an overview of the epigenetic testing landscape in cancer by examining commercially available epigenetic-based in vitro diagnostic tests for colon, breast, cervical, glioblastoma, lung cancers, and for cancers of unknown origin. We compile current commercial epigenetic tests based on epigenetic biomarkers (i.e., DNA methylation, miRNAs, and histones) that can actually be implemented into clinical practice.
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Affiliation(s)
- Jesús Beltrán-García
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain.,INCLIVA Biomedical Research Institute, Valencia, Spain.,Department of Physiology, School of Medicine and Dentistry, Universitat de València (UV), Valencia, Spain
| | - Rebeca Osca-Verdegal
- INCLIVA Biomedical Research Institute, Valencia, Spain.,Department of Physiology, School of Medicine and Dentistry, Universitat de València (UV), Valencia, Spain
| | - Salvador Mena-Mollá
- Department of Physiology, School of Medicine and Dentistry, Universitat de València (UV), Valencia, Spain.,EpiDisease S.L. Spin-Off of CIBERER (ISCIII), Valencia, Spain
| | - José Luis García-Giménez
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain.,INCLIVA Biomedical Research Institute, Valencia, Spain.,Department of Physiology, School of Medicine and Dentistry, Universitat de València (UV), Valencia, Spain.,EpiDisease S.L. Spin-Off of CIBERER (ISCIII), Valencia, Spain
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