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Saputra HA, Karim MM. Fundamentals and research progression on electrochemical sensing of colorectal cancer. Mikrochim Acta 2025; 192:355. [PMID: 40369291 DOI: 10.1007/s00604-025-07207-9] [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: 03/20/2025] [Accepted: 04/30/2025] [Indexed: 05/16/2025]
Abstract
Colorectal cancer (CRC) is a type of malignant disease that affects the large intestine (colon) and rectum. The CRC is among the causes of the highest mortality rates worldwide, so its rapid and sensitive early diagnosis is substantial. In the last few decades, CRC detection by electrochemical biosensors has progressed significantly due to their amenability and cost-effectiveness. Various electrochemical sensing strategies have been implemented, involving CRC biomarkers, such as protein, gene, or even CRC cells, that play a crucial role in screening tests, treatment, and prognosis. Electrochemical sensors are favored in this regard, owing to their ability to provide real-time, on-site detection with a straightforward preparation of samples. The present work provides an overview from the basic concepts to the recent research advances in electrochemical CRC biosensors for the management of patients. The review covers the importance of CRC detection, an introduction to electrochemical sensors, and cutting-edge electrochemical CRC biosensors. Further, challenges, limitations, and future research directions in developing and applying electrochemical sensing tools for CRC biomarkers are also comprehensively discussed. By consolidating the current research status, the present work aims to inspire further innovation in the development of electrochemical CRC biosensors. The insights presented here are expected to contribute to advancing more efficient, accessible diagnostic devices for CRC in the future.
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Affiliation(s)
| | - Md Mobarok Karim
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
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Hong X, Miao K, Cao W, Lv J, Yu C, Huang T, Sun D, Liao C, Pang Y, Hu R, Pang Z, Yu M, Wang H, Wu X, Liu Y, Gao W, Li L. Association of psychological distress and DNA methylation: A 5-year longitudinal population-based twin study. Psychiatry Clin Neurosci 2024; 78:51-59. [PMID: 37793011 DOI: 10.1111/pcn.13606] [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: 07/13/2023] [Revised: 09/25/2023] [Accepted: 09/28/2023] [Indexed: 10/06/2023]
Abstract
AIM To identify the psychological distress (PD)-associated 5'-cytosine-phosphate-guanine-3' sites (CpGs), and investigate the temporal relationship between dynamic changes in DNA methylation (DNAm) and PD. METHODS This study included 1084 twins from the Chinese National Twin Register (CNTR). The CNTR conducted epidemiological investigations and blood withdrawal twice in 2013 and 2018. These included twins were used to perform epigenome-wide association studies (EWASs) and to validate the previously reported PD-associated CpGs selected from previous EWASs in PubMed, Embase, and the EWAS catalog. Next, a cross-lagged study was performed to examine the temporality between changes in DNAm and PD in 308 twins who completed both 2013 and 2018 surveys. RESULTS The EWAS analysis of our study identified 25 CpGs. In the validation analysis, 741 CpGs from 29 previous EWASs on PD were selected for validation, and 101 CpGs were validated to be significant at a false discovery rate <0.05. The cross-lagged analysis found a unidirectional path from PD to DNAm at 14 CpGs, while no sites showed significance from DNAm to PD. CONCLUSIONS This study identified and validated PD-related CpGs in a Chinese twin population, and suggested that PD may be the cause of changes in DNAm over time. The findings provide new insights into the molecular mechanisms underlying PD pathophysiology.
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Affiliation(s)
- Xuanming Hong
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Ke Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Weihua Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Chunxiao Liao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Runhua Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Zengchang Pang
- Qingdao Center for Disease Control and Prevention, Qingdao, China
| | - Min Yu
- Zhejiang Center for Disease Control and Prevention, Hangzhou, China
| | - Hua Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, China
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention, Chengdu, China
| | - Yu Liu
- Heilongjiang Center for Disease Control and Prevention, Harbin, China
| | - Wenjing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, China
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Bagheri R, Ghorbian M, Ghorbian S. Tumor circulating biomarkers in colorectal cancer. Cancer Treat Res Commun 2023; 38:100787. [PMID: 38194840 DOI: 10.1016/j.ctarc.2023.100787] [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: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/21/2023] [Indexed: 01/11/2024]
Abstract
CRC is a major global health concern and is responsible for a significant number of cancer-related deaths each year. The successful treatment of CRC becomes more difficult when it goes undetected until it has advanced to a later stage. Diagnostic biomarkers can play a critical role in the early detection of CRC, which leads to improved patient outcomes and increased survival rates. It is important to develop reliable biomarkers for the early detection of CRC to enable timely diagnosis and treatment. To date, CRC detection methods such as endoscopy, blood, and stool tests are imperfect and often only identify cases in the later stages of the disease. To overcome these limitations, researchers are turning to molecular biomarkers as a promising avenue for improving CRC detection. Diagnostic information can be provided more reliably through a noninvasive approach using biomarkers such as mRNA, circulating cell-free DNA, micro-RNA, long non-coding RNA, and proteins. These biomarkers can be found in blood, tissue, feces, and volatile organic compounds. The identification of molecular biomarkers with high sensitivity and specificity for early detection of CRC that are safe, cost-effective, and easily measurable remains a significant challenge for researchers. In this article, we will explore the latest advancements in blood-based diagnostic biomarkers for CRC and their potential impact on improving patient survival rates.
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Affiliation(s)
- Raana Bagheri
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran
| | - Mohsen Ghorbian
- Department of Computer Engineering, Qom Branch, Islamic Azad University, Qom, Iran
| | - Saeid Ghorbian
- Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran.
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Hong X, Miao K, Cao W, Lv J, Yu C, Huang T, Sun D, Liao C, Pang Y, Pang Z, Yu M, Wang H, Wu X, Liu Y, Gao W, Li L. Association Between DNA Methylation and Blood Pressure: A 5-Year Longitudinal Twin Study. Hypertension 2023; 80:169-181. [PMID: 36345830 DOI: 10.1161/hypertensionaha.122.19953] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Previous EWASs (Epigenome-Wide Association Studies) have reported hundreds of blood pressure (BP) associated 5'-cytosine-phosphate-guanine-3' (CpG) sites. However, their results were inconsistent. Longitudinal observations on the temporal relationship between DNA methylation and BP are lacking. METHODS A candidate CpG site association study for BP was conducted on 1072 twins in the Chinese National Twin Registry. PubMed and EMBASE were searched for candidate CpG sites. Cross-lagged models were used to assess the temporal relationship between BP and DNA methylation in 308 twins who completed 2 surveys in 2013 and 2018. Then, the significant cross-lagged associations were validated by adopting the Inference About Causation From Examination of Familial Confounding approach. Finally, to evaluate the cumulative effects of DNA methylation on the progression of hypertension, we established methylation risk scores based on BP-associated CpG sites and performed Markov multistate models. RESULTS 16 and 20 CpG sites were validated to be associated with systolic BP and diastolic BP, respectively. In the cross-lagged analysis, we detected that methylation of 2 CpG sites could predict subsequent systolic BP, and systolic BP predicted methylation at another 3 CpG sites. For diastolic BP, methylation at 3 CpG sites had significant cross-lagged effects for predicting diastolic BP levels, while the prediction from the opposite direction was observed at one site. Among these, 3 associations were validated in the Inference About Causation From Examination of Familial Confounding analysis. Using the Markov multistate model, we observed that methylation risk scores were associated with the development of hypertension. CONCLUSIONS Our findings suggest the significance of DNA methylation in the development of hypertension.
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Affiliation(s)
- Xuanming Hong
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Ke Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Weihua Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Chunxiao Liao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Zengchang Pang
- Qingdao Center for Disease Control and Prevention, China (Z.P.)
| | - Min Yu
- Zhejiang Center for Disease Control and Prevention, Hangzhou, China (M.Y.)
| | - Hua Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, China (H.W.)
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention, Chengdu, China (X.W.)
| | - Yu Liu
- Heilongjiang Center for Disease Control and Prevention, Harbin, China (Y.L.)
| | - Wenjing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, China (X.H., K.M., W.C., J.L., C.Y., T.H., D.S., C.L., Y.P., W.G., L.L.)
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Hong X, Wu Z, Cao W, Lv J, Yu C, Huang T, Sun D, Liao C, Pang Y, Pang Z, Cong L, Wang H, Wu X, Liu Y, Gao W, Li L. Longitudinal Association of DNA Methylation With Type 2 Diabetes and Glycemic Traits: A 5-Year Cross-Lagged Twin Study. Diabetes 2022; 71:2804-2817. [PMID: 36170668 DOI: 10.2337/db22-0513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 09/20/2022] [Indexed: 01/11/2023]
Abstract
Investigators of previous cross-sectional epigenome-wide association studies (EWAS) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWAS have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNA methylation (DNAm) could be modified by smoking, drinking, and glycemic traits, which have broad impacts on genome-wide DNAm and result in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as twins are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and Embase for EWAS, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c, and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17, and 16 CpG sites from previous studies were validated for T2DM, HbA1c, and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 for 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. A total of 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none were from the other cross-lagged direction, indicating that CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed to explore the mediation effects of DNAm on the associations of smoking, drinking, and glycemic traits with T2DM. No significant mediations of DNAm in the associations linking smoking and drinking with T2DM were found. In contrast, our study suggested a potential role of DNAm of cg19693031, cg00574958, and cg04816311 in mediating the effect of altered glycemic traits on T2DM.
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Affiliation(s)
- Xuanming Hong
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zhiyu Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Weihua Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Chunxiao Liao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zengchang Pang
- Qingdao Center for Disease Control and Prevention, Qingdao, China
| | - Liming Cong
- Zhejiang Center for Disease Control and Prevention, Hangzhou, China
| | - Hua Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, China
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention, Chengdu, China
| | - Yu Liu
- Heilongjiang Center for Disease Control and Prevention, Harbin, China
| | - Wenjing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
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Guo Q, Hua Y. The assessment of circulating cell-free DNA as a diagnostic tool for breast cancer: an updated systematic review and meta-analysis of quantitative and qualitative ssays. Clin Chem Lab Med 2021; 59:1479-1500. [PMID: 33951758 DOI: 10.1515/cclm-2021-0193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/23/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES This updated meta-analysis aimed to assess the diagnostic accuracy of circulating cell-free DNA (cfDNA) in breast cancer (BC). CONTENT An extensive systematic search was performed in PubMed, Scopus, Embase, and Science Direct databases to retrieve all related literature. Various diagnostic estimates, including sensitivity (SE), specificity (SP), likelihood ratios (LRs), diagnostic odds ratio (DOR), and area under the curve (AUC) of summary receiver operating characteristic (sROC) curve, were also calculated using bivariate linear mixed models. SUMMARY In this meta-analysis, 57 unique articles (130 assays) on 4246 BC patients and 2,952 controls, were enrolled. For quantitative approaches, pooled SE, SP, PLR, NLR, DOR, and AUC were obtained as 0.80, 0.88, 6.7, 0.23, 29, and 0.91, respectively. Moreover, for qualitative approaches, pooled SE and SP for diagnostic performance were obtained as 0.36 and 0.98, respectively. In addition, PLR was 14.9 and NLR was 0.66. As well, the combined DOR was 23, and the AUC was 0.79. OUTLOOK Regardless of promising SE and SP, analysis of LRs suggested that quantitative assays are not robust enough neither for BC confirmation nor for its exclusion. On the other hand, qualitative assays showed satisfying performance only for confirming the diagnosis of BC, but not for its exclusion. Furthermore, qualitative cfDNA assays showed a better diagnostic performance in patients at the advanced stage of cancer, which represented no remarkable clinical significance as a biomarker for early detection.
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Affiliation(s)
- Qingfeng Guo
- Department of General Surgery, Affiliated Hospital of Jiangnan University (Original Area of Wuxi No. 3 People's Hospital), Wuxi, P.R. China
| | - Yuming Hua
- Department of General Surgery, Affiliated Hospital of Jiangnan University (Original Area of Wuxi No. 3 People's Hospital), Wuxi, P.R. China
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Zhang J, Yuan Y, Gao S, Zhao X, Li H. Diagnostic performance of circulating cell-free DNA for hepatocellular carcinoma: a systematic review and meta-analysis. Biomark Med 2021; 15:219-239. [PMID: 33470842 DOI: 10.2217/bmm-2020-0334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 12/09/2020] [Indexed: 12/26/2022] Open
Abstract
Background: We aimed to assess the diagnostic performance of circulating cell-free DNA (cfDNA) in hepatocellular carcinoma (HCC). Materials & methods: After a systematic literature search bivariate linear mixed models were used to integrate sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. The area under receiver operating characteristics curves of the included studies was used to estimate the diagnostic value. Results: Thirty-eight articles enrolled in quantitative synthesis. In overall analysis the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and area under receiver operating characteristics curves for cfDNA in distinguishing HCC patients from healthy controls were 0.54, 0.90, 5.23, 0.51, 10.27 and 0.82, respectively. Conclusion: This study suggests that cfDNA has a promising diagnostic accuracy in detection of HCC.
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Affiliation(s)
- Jinmei Zhang
- Department of Infectious Diseases, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Yuan Yuan
- Department of Infectious Diseases, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Shuxia Gao
- GI Medicine Department, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Xue Zhao
- Respiratory Department, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Hong Li
- Department of Infectious Diseases, Weifang Yidu Central Hospital, Qingzhou 262500, China
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Abstract
PURPOSE OF REVIEW In the United States, only 67% of patients are up to date with colorectal cancer (CRC) screening. While colonoscopy is highly sensitive and specific for CRC and precursor lesion detection and removal, it is invasive, expensive and resource heavy. Hence, there is an unfulfilled need for multiple modality CRC screening that can improve current CRC screening rates and may be resource effective strategies when used in conjunction with a colonoscopy program. Our review highlights the complementary, often underutilized, noninvasive CRC screening methods with a focus on performance, risks, benefits, and recent updates. RECENT FINDINGS Studies demonstrate that fecal immunochemical testing (FIT) is superior to guaiac-based fecal occult blood tests for CRC screening. Studies show superiority of multitarget stool DNA test to FIT in sensitivity, though with concern for decreased specificity in setting of one-time tests. Technical advances continue to improve accuracy of colon capsule endoscopy. There are ongoing studies to characterize often difficult-to-detect high-risk lesions in computed tomography colonography. Septin 9 continues to have suboptimal accuracy for CRC screening, but has been shown to be associated with more advanced, invasive CRC stages. SUMMARY There are ongoing advances in noninvasive screening modalities for CRC; these should be considered as alternatives to colonoscopy in specific patient populations.
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Affiliation(s)
- Susan Lou
- Division of Gastroenterology, Department of Medicine, University of Minnesota
| | - Aasma Shaukat
- Division of Gastroenterology, Department of Medicine, University of Minnesota
- Division of Gastroenterology, Department of Medicine, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota, USA
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Cohen JD, Diergaarde B, Papadopoulos N, Kinzler KW, Schoen RE. Tumor DNA as a Cancer Biomarker through the Lens of Colorectal Neoplasia. Cancer Epidemiol Biomarkers Prev 2020; 29:2441-2453. [PMID: 33033144 PMCID: PMC7710619 DOI: 10.1158/1055-9965.epi-20-0549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/06/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022] Open
Abstract
Biomarkers have a wide range of applications in the clinical management of cancer, including screening and therapeutic management. Tumor DNA released from neoplastic cells has become a particularly active area of cancer biomarker development due to the critical role somatic alterations play in the pathophysiology of cancer and the ability to assess released tumor DNA in accessible clinical samples, in particular blood (i.e., liquid biopsy). Many of the early applications of tumor DNA as a biomarker were pioneered in colorectal cancer due to its well-defined genetics and common occurrence, the effectiveness of early detection, and the availability of effective therapeutic options. Herein, in the context of colorectal cancer, we describe how the intended clinical application dictates desired biomarker test performance, how features of tumor DNA provide unique challenges and opportunities for biomarker development, and conclude with specific examples of clinical application of tumor DNA as a biomarker with particular emphasis on early detection.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- Joshua D Cohen
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kenneth W Kinzler
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Robert E Schoen
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Hariharan R, Jenkins M. Utility of the methylated SEPT9 test for the early detection of colorectal cancer: a systematic review and meta-analysis of diagnostic test accuracy. BMJ Open Gastroenterol 2020; 7:e000355. [PMID: 32128229 PMCID: PMC7039590 DOI: 10.1136/bmjgast-2019-000355] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/23/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Background Circulating tumour DNA from colorectal cancer (CRC) is a biomarker for early detection of the disease and therefore potentially useful for screening. One such biomarker is the methylated SEPT9 (mSEPT9) gene, which occurs during CRC tumourigenesis. This systematic review and meta-analysis aims to establish the sensitivity, specificity and accuracy of mSEPT9 tests for the early diagnosis of CRC. Methods A systematic search of the relevant literature was conducted using Medline and Embase databases. Data were extracted from the eligible studies and analysed to estimate pooled sensitivity, specificity and diagnostic test accuracy. Results Based on 19 studies, the pooled estimates (and 95% CIs) for mSEPT9 to detect CRC were: sensitivity 69% (62-75); specificity 92% (89-95); positive likelihood ratio 9.1 (6.1-13.8); negative likelihood ratio 0.34 (0.27-0.42); diagnostic OR 27 (15-48) and area under the curve 0.89 (0.86-0.91). The test has a positive predictive value of 2.6% and negative predictive value of 99.9% in an average risk population (0.3% CRC prevalence), and 9.5% (positive predictive value) and 99.6% (negative predictive value) in a high-risk population (1.2% CRC prevalence). Conclusion The mSEPT9 test has high specificity and moderate sensitivity for CRC and is therefore a potential alternative screening method for those declining faecal immunochemical test for occult blood (FIT) or other screening modalities. However, it is limited by its poor diagnostic performance for precancerous lesions (advanced adenomas and polyps) and its relatively high costs, and little is known about its acceptability to those declining to use the FIT.
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Affiliation(s)
- Rohit Hariharan
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Victoria, Australia
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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: 77] [Impact Index Per Article: 15.4] [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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Ladabaum U, Dominitz JA, Kahi C, Schoen RE. Strategies for Colorectal Cancer Screening. Gastroenterology 2020; 158:418-432. [PMID: 31394083 DOI: 10.1053/j.gastro.2019.06.043] [Citation(s) in RCA: 389] [Impact Index Per Article: 77.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/06/2019] [Accepted: 06/24/2019] [Indexed: 12/11/2022]
Abstract
The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.
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Affiliation(s)
- Uri Ladabaum
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
| | - Jason A Dominitz
- Gastroenterology Section, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Charles Kahi
- Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana
| | - Robert E Schoen
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
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He H, Li J, Xu M, Kan Z, Gao Y, Yuan C. Expression of septin 2 and association with clinicopathological parameters in colorectal cancer. Oncol Lett 2019; 18:2376-2383. [PMID: 31402940 PMCID: PMC6676678 DOI: 10.3892/ol.2019.10528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/07/2019] [Indexed: 12/16/2022] Open
Abstract
Septin 2 (SEPT2) is a tumor-related gene belonging to the SEPT family that affects the cellular processes of hepatoma carcinoma cells, glioblastoma cells and mesangial cells and is highly expressed in breast cancer, biliary tract cancer and acute myeloid leukemia. Colorectal cancer (CRC) is the third most common type of malignancy in humans. In the present study, Oncomine database was used to compare the expression pattern of SEPT2 mRNA between CRC and normal tissues. Additionally, protein expression in 90 pairs of CRC and paracancerous tissues was analyzed by western blotting and immunohistochemistry (IHC). The results showed that SEPT2 was highly expressed in CRC tissues at the mRNA and protein levels. SEPT2 expression quantified by IHC was associated with lymph node metastasis, the degree of differentiation and TNM staging. Increased SEPT2 wass associated with reduced overall survival (OS) according to Kaplan-Meier analysis. COX proportional hazard analysis indicated that SEPT2 was an independent factor that influenced the OS of patients with CRC. Therefore, SEPT2 was associated with the occurrence, progression and prognosis of CRC and thus, may be a marker and prognostic indicator of CRC.
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Affiliation(s)
- Haoyu He
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Junjun Li
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Meng Xu
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Ziliang Kan
- Graduate School, Singapore Management University, Singapore 178903, Republic of Singapore
| | - Yang Gao
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Caijun Yuan
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
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James NE, Cantillo E, Yano N, Chichester CO, DiSilvestro PA, Hovanesian V, Rao RSP, Kim KK, Moore RG, Ahsan N, Ribeiro JR. Septin-2 is overexpressed in epithelial ovarian cancer and mediates proliferation via regulation of cellular metabolic proteins. Oncotarget 2019; 10:2959-2972. [PMID: 31105878 PMCID: PMC6508204 DOI: 10.18632/oncotarget.26836] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 03/23/2019] [Indexed: 02/06/2023] Open
Abstract
Epithelial Ovarian Cancer (EOC) is associated with dismal survival rates due to the fact that patients are frequently diagnosed at an advanced stage and eventually become resistant to traditional chemotherapeutics. Hence, there is a crucial need for new and innovative therapies. Septin-2, a member of the septin family of GTP binding proteins, has been characterized in EOC for the first time and represents a potential future target. Septin-2 was found to be overexpressed in serous and clear cell human patient tissue compared to benign disease. Stable septin-2 knockdown clones developed in an ovarian cancer cell line exhibited a significant decrease in proliferation rates. Comparative label-free proteomic analysis of septin-2 knockdown cells revealed differential protein expression of pathways associated with the TCA cycle, acetyl CoA, proteasome and spliceosome. Further validation of target proteins indicated that septin-2 plays a predominant role in post-transcriptional and translational modifications as well as cellular metabolism, and suggested the potential novel role of septin-2 in promoting EOC tumorigenesis through these mechanisms.
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Affiliation(s)
- Nicole E. James
- Division of Gynecologic Oncology, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA
| | - Evelyn Cantillo
- Division of Gynecologic Oncology, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA
| | - Naohiro Yano
- Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, RI, USA
| | - Clinton O. Chichester
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA
| | - Paul A. DiSilvestro
- Division of Gynecologic Oncology, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA
- Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
| | | | - R. Shyama Prasad Rao
- Biostatistics and Bioinformatics Division, Yenepoya Research Center, Yenepoya University, Mangalore, India
| | - Kyukwang K. Kim
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Richard G. Moore
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Nagib Ahsan
- Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI, USA
- Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Jennifer R. Ribeiro
- Division of Gynecologic Oncology, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA
- Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
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Affiliation(s)
- Dan Li
- Corresponding author. Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, CA 95051, USA.
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Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer. DISEASE MARKERS 2018; 2018:6437104. [PMID: 29849824 PMCID: PMC5937566 DOI: 10.1155/2018/6437104] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 03/07/2018] [Indexed: 02/06/2023]
Abstract
Identification of early-stage tumor and monitoring therapeutic efficacy and recurrence or metastasis of colorectal cancer (CRC) are urgently warranted for improving the outcome of CRC patients and reducing the disease-related mortality. In this study, we evaluated the diagnostic value of cell-free circulating methylated SEPT9 (mSEPT9) for CRC and beyond CRC and examined the potentiality of mSEPT9 in assessing therapeutic efficacy and monitoring recurrence of CRC. Our results confirmed the favorable diagnostic value of plasma mSEPT9 for CRC, with a sensitivity of 61.22% (95% confidence interval (CI): 51.33%–70.27%) and specificity of 93.7% (95% CI: 91.09%–95.57%) using 2/3 algorithm. The positive rate of mSEPT9 in CRC was correlated with tumor size, histological grade, and general histological type (P < 0.05). Beyond CRC, gastric cancer patients also presented a high positive rate of plasma mSEPT9 (70%). The conversions between preoperative and postoperative plasma mSEPT9 reflected the therapeutic efficacy of curatively intended surgery for CRC patients. The persistent positivity of plasma mSEPT9 after surgery (within 7–14 days) was highly associated with impending recurrences or metastases (within one year), with a sensitivity of 100%. Postoperative mSEPT9 status during follow-up also provided valuable indication for CRC recurrence or metastases, with a good consistency (kappa = 0.818, P = 0.001). Our results verified the reliability of plasma mSEPT9 as a biomarker for noninvasive diagnosis of CRC. More significantly, we revealed its valuable role in appraising CRC therapeutic efficacy and monitoring CRC recurrences or metastases. Further studies with larger sample sizes are needed to verify and elucidate the clinical utility of the promising findings.
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Potential of quantitative SEPT9 and SHOX2 methylation in plasmatic circulating cell-free DNA as auxiliary staging parameter in colorectal cancer: a prospective observational cohort study. Br J Cancer 2018; 118:1217-1228. [PMID: 29610456 PMCID: PMC5943265 DOI: 10.1038/s41416-018-0035-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 02/06/2023] Open
Abstract
Background Septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) methylation in circulating cell-free DNA (ccfDNA) are powerful biomarkers for colorectal cancer (CRC) screening, as well as head and neck squamous cell carcinoma staging and monitoring. In the present study, we investigated SEPT9 and SHOX2 ccfDNA methylation as auxiliary pre and post-therapeutic staging parameters in CRC patients. Methods ccfDNA methylation was quantified in 184 prospectively enrolled patients prior to and 3–10 days after surgery, and biomarker levels were associated with clinico-pathological parameters. Results Pre-therapeutic levels of SHOX2 and SEPT9 ccfDNA methylation were strongly associated with Union for International Cancer Control (UICC) stages, tumour (T), nodal (N), and metastasis (M) categories, and histological grade (all P ≤ 0.001), as well as lymphatic invasion and extracapsular lymph node extension (all P< 0.05). Post-therapeutic SHOX2 and SEPT9 ccfDNA methylation levels correlated with UICC stage (all P <0.01). SEPT9 ccfDNA methylation further allowed for an accurate pre- and post-therapeutic detection of distant metastases (AUCpre-therapeutic = 0.79 (95%CI 0.69–0.89), AUCpost-therapeutic = 0.93 (95% CI 0.79–1.0)). Conclusions DNA methylation analysis in plasma is a powerful pre and post-therapeutic diagnostic tool for CRC and may add valuable information to current TNM staging, thereby holding the potential to assist in the development of individually tailored treatment protocols.
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