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Eboshida N, Hamada A, Higaki M, Obayashi F, Ito N, Yamasaki S, Tani R, Shintani T, Koizumi K, Yanamoto S. Potential role of circulating tumor cells and cell-free DNA as biomarkers in oral squamous cell carcinoma: A prospective single-center study. PLoS One 2024; 19:e0309178. [PMID: 39729421 DOI: 10.1371/journal.pone.0309178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/06/2024] [Indexed: 12/29/2024] Open
Abstract
Metastasis in patients with oral squamous cell carcinoma has been associated with a poor prognosis. However, sensitive and reliable tests for monitoring their occurrence are unavailable, with the exception of PET-CT. Circulating tumor cells and cell-free DNA have emerged as promising biomarkers for determining treatment efficacy and as prognostic predictors in solid tumors such as breast cancer and colorectal cancer. Hence, this study aimed to determine the potential role of liquid biopsy, circulating tumor cells, and cell-free DNA as biomarkers of oral squamous cell carcinoma. Thirteen patients with primary oral squamous cell carcinoma who visited our hospital between 2022 and 2023 were recruited, and plasma samples were collected from each patient preoperatively and postoperatively. We examined the relationship between the prognosis, the number of circulating tumor cells per four milliliters of peripheral blood, and the amount of cell-free DNA per milliliter of serum or the gene mutation in cell-free DNA. We observed no correlation between the number of preoperative circulating tumor cells and metastatic events. However, the number of circulating tumor cell clusters or the amount of preoperative cell-free DNA in metastatic cases was higher than that in non-metastatic cases. In oral squamous cell carcinoma, circulating tumor cell clusters or cell-free DNA levels may help inform management decisions regarding metastasis. However, further studies are required to provide a possible window for therapeutic interventions.
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Affiliation(s)
- Natsuki Eboshida
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsuko Hamada
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mirai Higaki
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fumitaka Obayashi
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Nanako Ito
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Sachiko Yamasaki
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryouji Tani
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoaki Shintani
- Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan
| | - Koichi Koizumi
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Souichi Yanamoto
- Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Tan WY, Nagabhyrava S, Ang-Olson O, Das P, Ladel L, Sailo B, He L, Sharma A, Ahuja N. Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology. Curr Issues Mol Biol 2024; 46:6533-6565. [PMID: 39057032 PMCID: PMC11276574 DOI: 10.3390/cimb46070390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 07/28/2024] Open
Abstract
Technological advancements in cell-free DNA (cfDNA) liquid biopsy have triggered exponential growth in numerous clinical applications. While cfDNA-based liquid biopsy has made significant strides in personalizing cancer treatment, the exploration and translation of epigenetics in liquid biopsy to clinical practice is still nascent. This comprehensive review seeks to provide a broad yet in-depth narrative of the present status of epigenetics in cfDNA liquid biopsy and its associated challenges. It highlights the potential of epigenetics in cfDNA liquid biopsy technologies with the hopes of enhancing its clinical translation. The momentum of cfDNA liquid biopsy technologies in recent years has propelled epigenetics to the forefront of molecular biology. We have only begun to reveal the true potential of epigenetics in both our understanding of disease and leveraging epigenetics in the diagnostic and therapeutic domains. Recent clinical applications of epigenetics-based cfDNA liquid biopsy revolve around DNA methylation in screening and early cancer detection, leading to the development of multi-cancer early detection tests and the capability to pinpoint tissues of origin. The clinical application of epigenetics in cfDNA liquid biopsy in minimal residual disease, monitoring, and surveillance are at their initial stages. A notable advancement in fragmentation patterns analysis has created a new avenue for epigenetic biomarkers. However, the widespread application of cfDNA liquid biopsy has many challenges, including biomarker sensitivity, specificity, logistics including infrastructure and personnel, data processing, handling, results interpretation, accessibility, and cost effectiveness. Exploring and translating epigenetics in cfDNA liquid biopsy technology can transform our understanding and perception of cancer prevention and management. cfDNA liquid biopsy has great potential in precision oncology to revolutionize conventional ways of early cancer detection, monitoring residual disease, treatment response, surveillance, and drug development. Adapting the implementation of liquid biopsy workflow to the local policy worldwide and developing point-of-care testing holds great potential to overcome global cancer disparity and improve cancer outcomes.
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Affiliation(s)
- Wan Ying Tan
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, USA
- Hematology & Oncology, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT 06030, USA
| | | | - Olivia Ang-Olson
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Paromita Das
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Luisa Ladel
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, USA
| | - Bethsebie Sailo
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Linda He
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Anup Sharma
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Nita Ahuja
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520-8000, USA
- Biological and Biomedical Sciences Program (BBS), Yale University, New Haven, CT 06520-8084, USA
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Tsai KY, Huang PS, Chu PY, Nguyen TNA, Hung HY, Hsieh CH, Wu MH. Current Applications and Future Directions of Circulating Tumor Cells in Colorectal Cancer Recurrence. Cancers (Basel) 2024; 16:2316. [PMID: 39001379 PMCID: PMC11240518 DOI: 10.3390/cancers16132316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/16/2024] Open
Abstract
The ability to predict or detect colorectal cancer (CRC) recurrence early after surgery enables physicians to apply appropriate treatment plans and different follow-up strategies to improve patient survival. Overall, 30-50% of CRC patients experience cancer recurrence after radical surgery, but current surveillance tools have limitations in the precise and early detection of cancer recurrence. Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and enter the bloodstream. These can provide real-time information on disease status. CTCs might become novel markers for predicting CRC recurrence and, more importantly, for making decisions about additional adjuvant chemotherapy. In this review, the clinical application of CTCs as a therapeutic marker for stage II CRC is described. It then discusses the utility of CTCs for monitoring cancer recurrence in advanced rectal cancer patients who undergo neoadjuvant chemoradiotherapy. Finally, it discusses the roles of CTC subtypes and CTCs combined with clinicopathological factors in establishing a multimarker model for predicting CRC recurrence.
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Affiliation(s)
- Kun-Yu Tsai
- Division of Colon and Rectal Surgery, New Taipei Municipal TuCheng Hospital, New Taipei City 23652, Taiwan
| | - Po-Shuan Huang
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Po-Yu Chu
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Thi Ngoc Anh Nguyen
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Hsin-Yuan Hung
- Division of Colon and Rectal Surgery, New Taipei Municipal TuCheng Hospital, New Taipei City 23652, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Chia-Hsun Hsieh
- College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, New Taipei Municipal Hospital, New Taipei City 23652, Taiwan
| | - Min-Hsien Wu
- Graduate Institute of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33302, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, New Taipei Municipal Hospital, New Taipei City 23652, Taiwan
- Department of Biomedical Engineering, Chang Gung University, Taoyuan City 33302, Taiwan
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Rendek T, Pos O, Duranova T, Saade R, Budis J, Repiska V, Szemes T. Current Challenges of Methylation-Based Liquid Biopsies in Cancer Diagnostics. Cancers (Basel) 2024; 16:2001. [PMID: 38893121 PMCID: PMC11171112 DOI: 10.3390/cancers16112001] [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: 04/23/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
In current clinical practice, effective cancer testing and screening paradigms are limited to specific types of cancer, exhibiting varying efficiency, acceptance, and adherence. Cell-free DNA (cfDNA) methylation profiling holds promise in providing information about the presence of malignity regardless of its type and location while leveraging blood-based liquid biopsies as a method to obtain analytical samples. However, technical difficulties, costs and challenges resulting from biological variations, tumor heterogeneity, and exogenous factors persist. This method exploits the mechanisms behind cfDNA release but faces issues like fragmentation, low concentrations, and high background noise. This review explores cfDNA methylation's origins, means of detection, and profiling for cancer diagnostics. The critical evaluation of currently available multi-cancer early detection methods (MCEDs) as well as tests targeting single genes, emphasizing their potential and limits to refine strategies for early cancer detection, are explained. The current methodology limitations, workflows, comparisons of clinically approved liquid biopsy-based methylation tests for cancer, their utilization in companion diagnostics as well as the biological limitations of the epigenetics approach are discussed, aiming to help healthcare providers as well as researchers to orient themselves in this increasingly complex and evolving field of diagnostics.
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Affiliation(s)
- Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Ondrej Pos
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | | | - Rami Saade
- 2nd Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Jaroslav Budis
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Tomas Szemes
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
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Dao J, Conway PJ, Subramani B, Meyyappan D, Russell S, Mahadevan D. Using cfDNA and ctDNA as Oncologic Markers: A Path to Clinical Validation. Int J Mol Sci 2023; 24:13219. [PMID: 37686024 PMCID: PMC10487653 DOI: 10.3390/ijms241713219] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The detection of circulating tumor DNA (ctDNA) in liquid biopsy samples as an oncological marker is being used in clinical trials at every step of clinical management. As ctDNA-based liquid biopsy kits are developed and used in clinics, companies work towards increased convenience, accuracy, and cost over solid biopsies and other oncological markers. The technology used to differentiate ctDNA and cell-free DNA (cfDNA) continues to improve with new tests and methodologies being able to detect down to mutant allele frequencies of 0.001% or 1/100,000 copies. Recognizing this development in technology, the FDA has recently given pre-market approval and breakthrough device designations to multiple companies. The purpose of this review is to look at the utility of measuring total cfDNA, techniques used to differentiate ctDNA from cfDNA, and the utility of different ctDNA-based liquid biopsy kits using relevant articles from PubMed, clinicaltrials.gov, FDA approvals, and company newsletters. Measuring total cfDNA could be a cost-effective, viable prognostic marker, but various factors do not favor it as a monitoring tool during chemotherapy. While there may be a place in the clinic for measuring total cfDNA in the future, the lack of standardization means that it is difficult to move forward with large-scale clinical validation studies currently. While the detection of ctDNA has promising standardized liquid biopsy kits from various companies with large clinical trials ongoing, their applications in screening and minimal residual disease can suffer from lower sensitivity. However, researchers are working towards solutions to these issues with innovations in technology, multi-omics, and sampling. With great promise, further research is needed before liquid biopsies can be recommended for everyday clinical management.
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Affiliation(s)
- Jonathan Dao
- Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Patrick J. Conway
- Mays Cancer Center, University of Texas Health, San Antonio, TX 78229, USA
- Graduate School of Biomedical Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Baskaran Subramani
- Mays Cancer Center, University of Texas Health, San Antonio, TX 78229, USA
- Graduate School of Biomedical Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Devi Meyyappan
- Mays Cancer Center, University of Texas Health, San Antonio, TX 78229, USA
| | - Sammy Russell
- Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Daruka Mahadevan
- Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health, San Antonio, TX 78229, USA
- Graduate School of Biomedical Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA
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6
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Kinetics of Plasma Cell-Free DNA under a Highly Standardized and Controlled Stress Induction. Cells 2023; 12:cells12040564. [PMID: 36831231 PMCID: PMC9954572 DOI: 10.3390/cells12040564] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Psychological stress affects the immune system and activates peripheral inflammatory pathways. Circulating cell-free DNA (cfDNA) is associated with systemic inflammation, and recent research indicates that cfDNA is an inflammatory marker that is sensitive to psychological stress in humans. The present study investigated the effects of acute stress on the kinetics of cfDNA in a within-subjects design. Twenty-nine males (mean age: 24.34 ± 4.08 years) underwent both the Trier Social Stress Test (TSST) and a resting condition. Blood samples were collected at two time points before and at 9 time points up to 105 min after both conditions. The cfDNA immediately increased 2-fold after the TSST and returned to baseline levels after 30 min after the test, showing that a brief psychological stressor was sufficient to evoke a robust and rapid increase in cfDNA levels. No associations were detected between perceived stress, whereas subjects with higher basal cfDNA levels showed higher increases. The rapid cfDNA regulation might be attributed to the transient activation of immune cells caused by neuroendocrine-immune activation. Further research is required to evaluate the reliability of cfDNA as a marker of neuroendocrine-immune activation, which could be used for diagnostics purposes or monitoring of treatment progression.
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Arisi MF, Dotan E, Fernandez SV. Circulating Tumor DNA in Precision Oncology and Its Applications in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23084441. [PMID: 35457259 PMCID: PMC9024503 DOI: 10.3390/ijms23084441] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/29/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient’s cfDNA depending on their tumor type and burden. The short half-life of ctDNA ensures that its detection captures tumor burden in real-time and offers a non-invasive method of repeatedly evaluating the genomic profile of a patient’s tumor. A challenge in ctDNA detection includes clonal hematopoiesis of indeterminate potential (CHIP), which can be distinguished from tumor variants using a paired whole-blood control. Most assays for ctDNA quantification rely on measurements of somatic variant allele frequency (VAF), which is a mutation-dependent method. Patients with certain types of solid tumors, including colorectal cancer (CRC), can have levels of cfDNA 50 times higher than healthy patients. ctDNA undergoes a precipitous drop shortly after tumor resection and therapy, and rising levels can foreshadow radiologic recurrence on the order of months. The amount of tumor bulk required for ctDNA detection is lower than that for computed tomography (CT) scan detection, with ctDNA detection preceding radiologic recurrence in many cases. cfDNA/ctDNA can be used for tumor molecular profiling to identify resistance mutations when tumor biopsy is not available, to detect minimal residual disease (MRD), to monitor therapy response, and for the detection of tumor relapse. Although ctDNA is not yet implemented in clinical practice, studies are ongoing to define the appropriate way to use it as a tool in the clinic. In this review article, we examine the general aspects of ctDNA, its status as a biomarker, and its role in the management of early (II–III) and late (IV; mCRC) stage colorectal cancer (CRC).
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Affiliation(s)
- Maria F. Arisi
- Sidney Kimmel Medical School, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Efrat Dotan
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA;
| | - Sandra V. Fernandez
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Correspondence:
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Raza A, Khan AQ, Inchakalody VP, Mestiri S, Yoosuf ZSKM, Bedhiafi T, El-Ella DMA, Taib N, Hydrose S, Akbar S, Fernandes Q, Al-Zaidan L, Krishnankutty R, Merhi M, Uddin S, Dermime S. Dynamic liquid biopsy components as predictive and prognostic biomarkers in colorectal cancer. J Exp Clin Cancer Res 2022; 41:99. [PMID: 35292091 PMCID: PMC8922757 DOI: 10.1186/s13046-022-02318-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/07/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. The diagnosis, prognosis and therapeutic monitoring of CRC depends largely on tissue biopsy. However, due to tumor heterogeneity and limitations such as invasiveness, high cost and limited applicability in longitudinal monitoring, liquid biopsy has gathered immense attention in CRC. Liquid biopsy has several advantages over tissue biopsy including ease of sampling, effective monitoring, and longitudinal assessment of treatment dynamics. Furthermore, the importance of liquid biopsy is signified by approval of several liquid biopsy assays by regulatory bodies indicating the powerful approach of liquid biopsy for comprehensive CRC screening, diagnostic and prognostics. Several liquid biopsy biomarkers such as novel components of the microbiome, non-coding RNAs, extracellular vesicles and circulating tumor DNA are extensively being researched for their role in CRC management. Majority of these components have shown promising results on their clinical application in CRC including early detection, observe tumor heterogeneity for treatment and response, prediction of metastases and relapse and detection of minimal residual disease. Therefore, in this review, we aim to provide updated information on various novel liquid biopsy markers such as a) oral microbiota related bacterial network b) gut microbiome-associated serum metabolites c) PIWI-interacting RNAs (piRNAs), microRNA(miRNAs), Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and d) circulating tumor DNAs (ctDNA) and circulating tumor cells (CTC) for their role in disease diagnosis, prognosis, treatment monitoring and their applicability for personalized management of CRC.
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Affiliation(s)
- Afsheen Raza
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Philipose Inchakalody
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Sarra Mestiri
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | | | - Takwa Bedhiafi
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Dina Moustafa Abo El-Ella
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Nassiba Taib
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shereena Hydrose
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shayista Akbar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Queenie Fernandes
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.,College of Medicine, Qatar University, Doha, Qatar
| | - Lobna Al-Zaidan
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Roopesh Krishnankutty
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
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Circulating tumour cells in the -omics era: how far are we from achieving the 'singularity'? Br J Cancer 2022; 127:173-184. [PMID: 35273384 PMCID: PMC9296521 DOI: 10.1038/s41416-022-01768-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/27/2022] [Accepted: 02/17/2022] [Indexed: 12/22/2022] Open
Abstract
Over the past decade, cancer diagnosis has expanded to include liquid biopsies in addition to tissue biopsies. Liquid biopsies can result in earlier and more accurate diagnosis and more effective monitoring of disease progression than tissue biopsies as samples can be collected frequently. Because of these advantages, liquid biopsies are now used extensively in clinical care. Liquid biopsy samples are analysed for circulating tumour cells (CTCs), cell-free DNA, RNA, proteins and exosomes. CTCs originate from the tumour, play crucial roles in metastasis and carry information on tumour heterogeneity. Multiple single-cell omics approaches allow the characterisation of the molecular makeup of CTCs. It has become evident that CTCs are robust biomarkers for predicting therapy response, clinical development of metastasis and disease progression. This review describes CTC biology, molecular heterogeneity within CTCs and the involvement of EMT in CTC dynamics. In addition, we describe the single-cell multi-omics technologies that have provided insights into the molecular features within therapy-resistant and metastasis-prone CTC populations. Functional studies coupled with integrated multi-omics analyses have the potential to identify therapies that can intervene the functions of CTCs.
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The relevance of liquid biopsy in surgical oncology: The application of perioperative circulating nucleic acid dynamics in improving patient outcomes. Surgeon 2021; 20:e163-e173. [PMID: 34362650 DOI: 10.1016/j.surge.2021.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND Liquid biopsy is gaining increasing clinical utility in the management of cancer patients. The main components of a liquid biopsy are circulating nucleic acids, circulating tumour cells and extracellular vesicles such as exosomes. Circulating nucleic acids including cell free DNA (cfDNA) and circulating tumour DNA (ctDNA) in particular have been the focus of recent attention as they have demonstrated excellent potential in cancer screening, provision of prognostic information and in genomic profiling of a tumour without the need for repeated tissue biopsies. The aim of this review was to explore the current evidence in relation to the use of liquid biopsy in the perioperative setting and identify ways in which liquid biopsy may be applied in the future. METHODS This narrative review is based on a comprehensive literature search up to the 1st of June 2020 for papers relevant to the application of liquid biopsy in surgical oncology, focusing particularly on the perioperative period. RESULTS Recent evidence has demonstrated that perioperative liquid biopsy can accurately stratify patients' risk of recurrence compared to conventional biomarkers. Attention to the perioperative dynamics of liquid biopsy components can potentially provide new understanding of the complex relationship between surgery and cancer outcome. In addition, careful evaluation of liquid biopsy components in the perioperative window may provide important diagnostic and therapeutic information for cancer patients. CONCLUSION The rapidly evolving concept of the liquid biopsy has the potential to become the cornerstone for decision making around surveillance and adjuvant therapies the era of personalised medicine.
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11
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Blumendeller C, Boehme J, Frick M, Schulze M, Rinckleb A, Kyzirakos C, Kayser S, Kopp M, Kelkenberg S, Pieper N, Bartsch O, Hadaschick D, Battke F, Stenzl A, Biskup S. Use of plasma ctDNA as a potential biomarker for longitudinal monitoring of a patient with metastatic high-risk upper tract urothelial carcinoma receiving pembrolizumab and personalized neoepitope-derived multipeptide vaccinations: a case report. J Immunother Cancer 2021; 9:jitc-2020-001406. [PMID: 33431630 PMCID: PMC7802705 DOI: 10.1136/jitc-2020-001406] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2020] [Indexed: 12/30/2022] Open
Abstract
Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Only limited data are available concerning therapeutic regimes and potential biomarkers for disease monitoring. Standard therapies often provide only insufficient treatment options. Hence, immunotherapies and complementary approaches, such as personalized neoepitope-derived multipeptide vaccine (PNMV), come into focus. In this context, genetic analysis of tumor tissue by whole exome sequencing represents an essential diagnostic step in order to calculate tumor mutational burden (TMB) and to reveal tumor-specific neoantigens. Furthermore, disease progression is essential to be monitored. Longitudinal screening of individually known mutations in plasma circulating tumor DNA (ctDNA) by the use of next-generation sequencing and digital droplet PCR (ddPCR) might be a promising method to fill this gap.Here, we present the case of a 55-year-old man who was diagnosed with high-risk metastatic UTUC in 2015. After initial surgery and palliative chemotherapy, he developed recurrence of the tumor. Genetic analysis revealed a high TMB of 41.2 mutations per megabase suggesting a potential success of immunotherapy. Therefore, in 2016, off-label treatment with the checkpoint-inhibitor pembrolizumab was started leading to strong regression of the disease. This therapy was then discontinued due to side effects and treatment with a previously produced PNMV was started that induced strong T cell responses. During both treatments, plasma Liquid Biopsies (pLBs) were performed to measure the number of mutated molecules per mL plasma (MM/mL) of a known tumor-specific variant in the MLH1 gene by ddPCR for longitudinal monitoring. Under treatment, MM/mL was constantly zero. A few months after all therapies had been discontinued, an increase of MM/mL was detected that persisted in the following pLBs. When MRI scans proved tumor recurrence, treatment with pembrolizumab was started again leading to a rapid decrease of MM/mL in the pLB to again zero. Treatment response was then also confirmed by MRI.This case shows that use of immunotherapy and PNMV might be a promising treatment option for patients with high-risk metastatic UTUC. Furthermore, measurement of individually known tumor mutations in plasma ctDNA by the use of pLB could be a very sensitive biomarker to longitudinally monitor disease.
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Affiliation(s)
| | - Julius Boehme
- Praxis für Humangenetik Tübingen, Tuebingen, Germany
| | | | | | | | | | - Simone Kayser
- Praxis für Humangenetik Tübingen, Tuebingen, Germany
| | | | | | | | | | | | | | - Arnulf Stenzl
- Department of Urology, University Hospital Tübingen, Tubingen, Germany
| | - Saskia Biskup
- Praxis für Humangenetik Tübingen, Tuebingen, Germany .,CeGaT GmbH, Tuebingen, Germany
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12
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Jiang X, Li W, Yang J, Wang S, Cao D, Yu M, Shen K, Bai J, Gao Y. Identification of Somatic Mutations in Papanicolaou Smear DNA and Plasma Circulating Cell-Free DNA for Detection of Endometrial and Epithelial Ovarian Cancers: A Pilot Study. Front Oncol 2021; 10:582546. [PMID: 33381450 PMCID: PMC7768029 DOI: 10.3389/fonc.2020.582546] [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: 07/12/2020] [Accepted: 11/02/2020] [Indexed: 11/13/2022] Open
Abstract
Objectives The aim of this study was to identify tumor-derived DNA from Papanicolaou (Pap) smear and plasma specimens collected from patients with endometrial cancer or atypical hyperplasia (EC/AH) or epithelial ovarian cancer (OC). Methods Tumor tissues, peripheral blood, and Pap smear samples were collected from patients with EC/AH and patients with epithelial OC. Somatic mutations of tumor specimens in EC/AH and OC were examined by whole-exome sequencing using a 127-driver gene panel from The Cancer Genome Atlas (TCGA). A nine-gene EC/AH panel and an eight-gene OC panel were established based on the identified significantly mutated genes in the EC/AH and OC tumor specimens. Circulating single-molecule amplification and resequencing technology (cSMART) was applied to evaluate somatic mutations in Pap smear DNA and plasma circulating cell-free DNA (ccfDNA) using the EC/AH and OC gene panels. Results In EC/AH group, there existed 22 tumors and 14 of the 22 tumors contributed hot spot mutations for the EC/AH nine-gene panel. In the Pap smear subgroup, all 21 Pap smears tested positive. Nine out of 11 (81.8%) identified the same gene mutations with their matched tumors and the remaining 10 Pap smears all tested positive. In the plasma subgroup, 10 out of 26 (38.5%) plasmas tested positive. One out of 13 (7.7%) identified the same gene mutation with its matched tumor and 5 out of the remaining 13 plasmas (38.5%) tested positive. In OC group, there existed 17 tumors and 16 of the 17 tumors contributed hot spot mutations for the OC eight-gene panel. In the Pap smear subgroup, all 11 Pap smears tested positive. Five out of 10 (50.0%) identified the same gene mutations with their matched tumors and the remaining one Pap smear also tested positive. In the plasma subgroup, all 22 plasmas tested positive. Ten out of 14 (71.4%) identified the same gene mutation with their matched tumors and the remaining 4 plasmas all tested positive. Conclusions Tumor-derived DNA can be detected in Pap smears and plasmas from patients with EC/AH or epithelial OC. Using a small gene-panel, early detection of EC/AH and OC might be promising. However, the value of plasma ccfDNA for EC/AH requires further investigation.
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Affiliation(s)
- Xuan Jiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.,Department of Obstetrics and Gynecology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Weihua Li
- Department of Obstetrics and Gynecology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Jiaxin Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Shuzhen Wang
- Department of Obstetrics and Gynecology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Dongyan Cao
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Mei Yu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Keng Shen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Jian Bai
- Berry Oncology Corporation, Beijing, China
| | - Yang Gao
- Berry Oncology Corporation, Beijing, China
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13
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Chen LY, Qi J, Xu HL, Lin XY, Sun YJ, Ju SQ. The Value of Serum Cell-Free DNA Levels in Patients With Schizophrenia. Front Psychiatry 2021; 12:637789. [PMID: 33859582 PMCID: PMC8042127 DOI: 10.3389/fpsyt.2021.637789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/08/2021] [Indexed: 01/05/2023] Open
Abstract
Background: Schizophrenia is a severe mental disorder, which has a major impact on the quality of life and imposes a huge burden on the family. However, the pathogenesis of schizophrenia remains unclear and there are no specific biomarkers. Therefore, we intend to explore whether cf-DNA levels are related to the occurrence and development of schizophrenia. Methods: We analyzed and compared the concentration of cf-DNA in 174 SZ patients and 100 matched healthy controls by using quantitative real-time PCR by amplifying the Alu repeats. Results: We found that cf-DNA levels in peripheral blood reliably distinguished SZ patients from healthy controls (P < 0.05). The ROC analysis also supports the above conclusion. By tracking the absolute concentration of serum cf-DNA in primary cases, we found a distinct increase before treatment with antipsychotics, which decreased progressively after treatment. Conclusions: The present work indicates that cf-DNA may improve the efficiency of disease diagnosis, and the level of cf-DNA plays a predictive role in the development of schizophrenia. By evaluating the level of cf-DNA, we might play a certain role in a more reasonable and standardized clinical treatment of schizophrenia.
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Affiliation(s)
- Ling-Yun Chen
- Center of Laboratory Medicine, Nantong Mental Health Center, Nantong, China
| | - Jing Qi
- Reaserch Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Hong-Lei Xu
- Neurology Laboratory, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiang-Yun Lin
- School of Public Health, Nantong University, Nantong, China
| | - Ya-Jun Sun
- Center of Laboratory Medicine, Nantong Mental Health Center, Nantong, China
| | - Shao-Qing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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14
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Polivka J, Windrichova J, Pesta M, Houfkova K, Rezackova H, Macanova T, Vycital O, Kucera R, Slouka D, Topolcan O. The Level of Preoperative Plasma KRAS Mutations and CEA Predict Survival of Patients Undergoing Surgery for Colorectal Cancer Liver Metastases. Cancers (Basel) 2020; 12:cancers12092434. [PMID: 32867151 PMCID: PMC7565270 DOI: 10.3390/cancers12092434] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA.
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Affiliation(s)
- Jiri Polivka
- Department of Histology and Embryology and Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Karlovarska 48, 30166 Pilsen, Czech Republic;
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
| | - Jindra Windrichova
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
| | - Martin Pesta
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
- Department of Biology, Charles University, Faculty of Medicine in Pilsen, alej Svobody 76, 32300 Pilsen, Czech Republic; (K.H.); (T.M.)
- Correspondence: ; Tel.: +420-377-593-261
| | - Katerina Houfkova
- Department of Biology, Charles University, Faculty of Medicine in Pilsen, alej Svobody 76, 32300 Pilsen, Czech Republic; (K.H.); (T.M.)
| | - Hana Rezackova
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
| | - Tereza Macanova
- Department of Biology, Charles University, Faculty of Medicine in Pilsen, alej Svobody 76, 32300 Pilsen, Czech Republic; (K.H.); (T.M.)
| | - Ondrej Vycital
- Department of Surgery, University Hospital in Pilsen, E. Beneše 13, 30599 Pilsen, Czech Republic;
| | - Radek Kucera
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
| | - David Slouka
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
| | - Ondrej Topolcan
- Laboratory of Immunoanalysis, University Hospital in Pilsen, E. Benese 13, 30599 Pilsen, Czech Republic; (J.W.); (H.R.); (R.K.); (D.S.); (O.T.)
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15
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Junca A, Tachon G, Evrard C, Villalva C, Frouin E, Karayan-Tapon L, Tougeron D. Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge. Cancers (Basel) 2020; 12:1482. [PMID: 32517177 PMCID: PMC7352444 DOI: 10.3390/cancers12061482] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and "liquid biopsy" allows detection of mutated circulating tumor DNA (ctDNA). This prospective study aims to evaluate the performance of RAS and BRAF-mutated ctDNA in detecting CRC and advanced adenomas (AA). METHODS One hundred and thirty patients who underwent colonoscopy for suspicion of colorectal lesion were included and divided into four groups: 20 CRC, 39 AA, 31 non-advanced adenoma and/or hyperplastic polyp(s) (NAA) and 40 with no lesion. Mutated ctDNA was analyzed by droplet digital PCR. RESULTS ctDNA was detected in 45.0% of CRC, in 2.6% of AA and none of the NAA and "no-lesion" groups. All patients with stage II to IV mutated CRC had detectable ctDNA (n = 8/8). Among the mutated AA, only one patient had detectable ctDNA (4.3%), maybe due to limited technical sensitivity or to a low rate of ctDNA or even the absence ctDNA in plasma. Specificity and sensitivity of KRAS- and BRAF-mutated ctDNA for the detection of all CRC and AA were 100% and 16.9%, respectively. CONCLUSIONS ctDNA had high sensitivity in detection of advanced mutated CRC but was unable to sensitively detect AA. ctDNA analysis was easy to perform and readily accepted by the population but requires combination with other circulating biomarkers before replacing iFOBT.
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Affiliation(s)
- Audelaure Junca
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Pathology, University Hospital of Poitiers, 86000 Poitiers, France
- Department of Cancer Biology, University Hospital of Poitiers, 86000 Poitiers, France;
| | - Gaëlle Tachon
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Cancer Biology, University Hospital of Poitiers, 86000 Poitiers, France;
- U1084, Institut national de la santé et de la recherche médicale (INSERM), 86000 Poitiers, France
| | - Camille Evrard
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Medical Oncology, University Hospital of Poitiers, 86000 Poitiers, France
| | - Claire Villalva
- Department of Cancer Biology, University Hospital of Poitiers, 86000 Poitiers, France;
| | - Eric Frouin
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Pathology, University Hospital of Poitiers, 86000 Poitiers, France
| | - Lucie Karayan-Tapon
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Cancer Biology, University Hospital of Poitiers, 86000 Poitiers, France;
- U1084, Institut national de la santé et de la recherche médicale (INSERM), 86000 Poitiers, France
| | - David Tougeron
- University of Poitiers, 86000 Poitiers, France; (A.J.); (G.T.); (C.E.); (E.F.); (L.K.-T.)
- Department of Medical Oncology, University Hospital of Poitiers, 86000 Poitiers, France
- Department of Gastroenterology, University Hospital of Poitiers, 86000 Poitiers, France
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16
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Oh HH, Joo YE. Novel biomarkers for the diagnosis and prognosis of colorectal cancer. Intest Res 2020; 18:168-183. [PMID: 31766836 PMCID: PMC7206347 DOI: 10.5217/ir.2019.00080] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/05/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is among the most common malignancies and remains a major cause of cancer-related death worldwide. Despite recent advances in surgical and multimodal therapies, the overall survival of advanced CRC patients remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. The underlying mechanisms of action resulting in cancer progression are beginning to unravel. The reported molecular and biochemical mechanisms that might contribute to the phenotypic changes in favor of carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, and immune surveillance inhibition. These events may contribute to the development and progression of cancer. A biomarker is a molecule that can be detected in tissue, blood, or stool samples to allow the identification of pathological conditions such as cancer. Thus, it would be beneficial to identify reliable and practical molecular biomarkers that aid in the diagnostic and therapeutic processes of CRC. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. Despite that, the identification of diagnostic, prognostic, and/or predictive biomarkers remains challenging, and previously identified biomarkers might be insufficient to be clinically applicable or offer high patient acceptability. Here, we discuss recent advances in the development of molecular biomarkers for their potential usefulness in early and less-invasive diagnosis, treatment, and follow-up of CRC.
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Affiliation(s)
- Hyung-Hoon Oh
- Department of Internal Medicine, 3rd Fleet Medical Corps, Republic of Korea Navy, Yeongam, Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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17
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Cervena K, Vodicka P, Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:100-129. [PMID: 31416571 DOI: 10.1016/j.mrrev.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
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18
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Hamfjord J, Guren TK, Dajani O, Johansen JS, Glimelius B, Sorbye H, Pfeiffer P, Lingjærde OC, Tveit KM, Kure EH, Pallisgaard N, Spindler KLG. Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy. Ann Oncol 2019; 30:1088-1095. [PMID: 31046124 DOI: 10.1093/annonc/mdz139] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION ClinicalTrials.gov, NCT00145314.
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Affiliation(s)
- J Hamfjord
- Department of Oncology, Oslo University Hospital, Oslo; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo
| | - T K Guren
- Department of Oncology, Oslo University Hospital, Oslo; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
| | - O Dajani
- Department of Oncology, Oslo University Hospital, Oslo
| | - J S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - B Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - H Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen; Department of Clinical Science, University of Bergen, Bergen, Norway
| | - P Pfeiffer
- Department of Oncology, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - O C Lingjærde
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Department of Computer Science, University of Oslo, Oslo
| | - K M Tveit
- Department of Oncology, Oslo University Hospital, Oslo; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo; K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - E H Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo; Faculty of Technology, Natural Sciences and Maritime Sciences, University of South-Eastern Norway, Bø in Telemark, Norway
| | - N Pallisgaard
- Department of Pathology, Zealand University Hospital, Roskilde
| | - K-L G Spindler
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Muluhngwi P, Valdes Jr R, Fernandez-Botran R, Burton E, Williams B, Linder MW. Cell-free DNA diagnostics: current and emerging applications in oncology. Pharmacogenomics 2019; 20:357-380. [DOI: 10.2217/pgs-2018-0174] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Liquid biopsy is a noninvasive dynamic approach for monitoring disease over time. It offers advantages including limited risks of blood sampling, opportunity for more frequent sampling, lower costs and theoretically non-biased sampling compared with tissue biopsy. There is a high degree of concordance between circulating tumor DNA mutations versus primary tumor mutations. Remote sampling of circulating tumor DNA can serve as viable option in clinical diagnostics. Here, we discuss the progress toward broad adoption of liquid biopsy as a diagnostic tool and discuss knowledge gaps that remain to be addressed.
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Affiliation(s)
- Penn Muluhngwi
- Department of Pathology & Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Roland Valdes Jr
- Department of Pathology & Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rafael Fernandez-Botran
- Department of Pathology & Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Eric Burton
- Department of Neurology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Brian Williams
- Department of Neurosurgery, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Mark W Linder
- Department of Pathology & Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
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20
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Abstract
The clinical utility of tissue biopsies in cancer management will continue to expand, especially with the evolving role of targeted therapies. "Liquid biopsy" refers to testing a patient's biofluid samples such as blood or urine to detect tumor-derived molecules and cells that can be used diagnostically and prognostically in the assessment of cancer. Many proof-of-concept and pilot studies have shown the clinical potential of liquid biopsies as diagnostic and prognostic markers which would provide a surrogate for the conventional "solid biopsy". In this review, we focus on three methods of liquid biopsy-circulating tumor cells, extracellular vesicles, and circulating tumor DNA-to provide a landscape view of their clinical applicability in cancer management and research.
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Affiliation(s)
- Matthew Scarlotta
- 1 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Cem Simsek
- 2 Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Amy K Kim
- 2 Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
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21
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Vymetalkova V, Cervena K, Bartu L, Vodicka P. Circulating Cell-Free DNA and Colorectal Cancer: A Systematic Review. Int J Mol Sci 2018; 19:ijms19113356. [PMID: 30373199 PMCID: PMC6274807 DOI: 10.3390/ijms19113356] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023] Open
Abstract
There is a strong demand for the identification of new biomarkers in colorectal cancer (CRC) diagnosis. Among all liquid biopsy analysts, cell-free circulating DNA (cfDNA) is probably the most promising tool with respect to the identification of minimal residual diseases, assessment of treatment response and prognosis, and identification of resistance mechanisms. Circulating cell-free tumor DNA (ctDNA) maintains the same genomic signatures that are present in the matching tumor tissue allowing for the quantitative and qualitative evaluation of mutation burdens in body fluids. Thus, ctDNA-based research represents a non-invasive method for cancer detection. Among the numerous possible applications, the diagnostic, predictive, and/or prognostic utility of ctDNA in CRC has attracted intense research during the last few years. In the present review, we will describe the different aspects related to cfDNA research and evidence from studies supporting its potential use in CRC diagnoses and the improvement of therapy efficacy. We believe that ctDNA-based research should be considered as key towards the introduction of personalized medicine and patient benefits.
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Affiliation(s)
- Veronika Vymetalkova
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00 Pilsen, Czech Republic.
| | - Klara Cervena
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
| | - Linda Bartu
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
| | - Pavel Vodicka
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00 Pilsen, Czech Republic.
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Gabriel E, Bagaria SP. Assessing the Impact of Circulating Tumor DNA (ctDNA) in Patients With Colorectal Cancer: Separating Fact From Fiction. Front Oncol 2018; 8:297. [PMID: 30128304 PMCID: PMC6088154 DOI: 10.3389/fonc.2018.00297] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/16/2018] [Indexed: 12/16/2022] Open
Abstract
Significant advances and increased awareness have been in made in the field of non-invasive liquid biopsies for cancer, spanning several malignancies from gastrointestinal, pulmonary, and other etiologies. Broadly, the genetic source material for liquid biopsies includes circulating tumor cells, cell-free circulating tumor DNA (ctDNA), or cell-free circulating tumor microRNA (mRNA). In this review, we specifically focus on ctDNA and its current role in colorectal cancer. While there are several commercially available assays that detect ctDNA, the utility of these products is still variable and therefore the clinical applications of ctDNA in the management of patients with cancer has yet to be determined. This is reflected by the recent joint review set forth by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP), clarifying and somewhat tempering the present role of ctDNA in patients with cancer. This review provides additional detail regarding ctDNA in the limited setting of colorectal cancer. The increasing importance and promise of ctDNA remains an area of active research, and further prospective studies may enhance the clinical utility of ctDNA in the future.
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Affiliation(s)
- Emmanuel Gabriel
- Section of Surgical Oncology, Department of Surgery, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Sanjay P Bagaria
- Section of Surgical Oncology, Department of Surgery, Mayo Clinic Florida, Jacksonville, FL, United States
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Saluja H, Karapetis CS, Pedersen SK, Young GP, Symonds EL. The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers. Front Oncol 2018; 8:275. [PMID: 30087854 PMCID: PMC6066577 DOI: 10.3389/fonc.2018.00275] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 07/02/2018] [Indexed: 01/10/2023] Open
Abstract
Gastrointestinal cancers, including oesophageal, gastric and colorectal cancers (CRC) have high rates of disease recurrence despite curative resection. There are a number of recent studies that have investigated the use of circulating tumor DNA (ctDNA) for prognostic value in these cancers. We reviewed studies that had been published prior to March 2018 that assessed the prognostic values of ctDNA in patients with oesophageal and gastric cancers, gastrointestinal stromal tumors (GIST) and CRC. We identified 63 eligible clinical studies that focussed on recurrence and survival. Studies assessed investigated various ctDNA biomarkers in patients with different stages of cancer undergoing surgical resection, chemotherapy and no treatment. For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed. Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival. Two studies demonstrated an association between ctDNA and recurrence and survival in GIST patients, but more studies are needed for this type of gastrointestinal cancer. A large proportion of the literature was on CRC which identified both somatic mutations and DNA methylation biomarkers to determine prognosis. ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival. While the use of non-invasive ctDNA biomarkers for prognosis is promising, larger studies are needed to validate the clinical utility for optimizing treatment and surveillance strategies to reduce mortality from gastrointestinal cancers.
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Affiliation(s)
- Hariti Saluja
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Department of Medicine, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Department of Oncology, Flinders Medical Centre, Bedford Park, SA, Australia
| | | | - Graeme P Young
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Erin L Symonds
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.,Bowel Health Service, Flinders Medical Centre, Bedford Park, SA, Australia
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24
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Chand M, Keller DS, Mirnezami R, Bullock M, Bhangu A, Moran B, Tekkis PP, Brown G, Mirnezami A, Berho M. Novel biomarkers for patient stratification in colorectal cancer: A review of definitions, emerging concepts, and data. World J Gastrointest Oncol 2018; 10:145-158. [PMID: 30079141 PMCID: PMC6068858 DOI: 10.4251/wjgo.v10.i7.145] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 04/22/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) treatment has become more personalised, incorporating a combination of the individual patient risk assessment, gene testing, and chemotherapy with surgery for optimal care. The improvement of staging with high-resolution imaging has allowed more selective treatments, optimising survival outcomes. The next step is to identify biomarkers that can inform clinicians of expected prognosis and offer the most beneficial treatment, while reducing unnecessary morbidity for the patient. The search for biomarkers in CRC has been of significant interest, with questions remaining on their impact and applicability. The study of biomarkers can be broadly divided into metabolic, molecular, microRNA, epithelial-to-mesenchymal-transition (EMT), and imaging classes. Although numerous molecules have claimed to impact prognosis and treatment, their clinical application has been limited. Furthermore, routine testing of prognostic markers with no demonstrable influence on response to treatment is a questionable practice, as it increases cost and can adversely affect expectations of treatment. In this review we focus on recent developments and emerging biomarkers with potential utility for clinical translation in CRC. We examine and critically appraise novel imaging and molecular-based approaches; evaluate the promising array of microRNAs, analyze metabolic profiles, and highlight key findings for biomarker potential in the EMT pathway.
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Affiliation(s)
- Manish Chand
- GENIE Centre, University College London, London W1W 7TS, United Kingdom
| | - Deborah S Keller
- Department of Surgery, Columbia University Medical Centre, New York, NY 10032, United States
| | - Reza Mirnezami
- Department of Surgery, Imperial College London, London SW7 2AZ, United Kingdom
| | - Marc Bullock
- Department of Surgery, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Aneel Bhangu
- Department of Surgery, University of Birmingham, Birmingham B15 2QU, United Kingdom
| | - Brendan Moran
- Department of Colorectal Surgery, North Hampshire Hospital, Basingstoke RG24 7AL, United Kingdom
| | - Paris P Tekkis
- Department of Colorectal Surgery, Royal Marsden Hospital and Imperial College London, London SW3 6JJ, United Kingdom
| | - Gina Brown
- Department of Radiology, Royal Marsden Hospital and Imperial College London, London SW3 6JJ, United Kingdom
| | - Alexander Mirnezami
- Department of Surgical Oncology, University of Southampton and NIHR, Southampton SO17 1BJ, United Kingdom
| | - Mariana Berho
- Department of Pathology, Cleveland Clinic Florida, Weston, FL 33331, United States
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25
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Oliveira IBDD, Hirata RDC. Circulating cell-free DNA as a biomarker in the diagnosis and prognosis of colorectal cancer. BRAZ J PHARM SCI 2018. [DOI: 10.1590/s2175-97902018000117368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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26
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Khatami F, Tavangar SM. Circulating tumor DNA (ctDNA) in the era of personalized cancer therapy. J Diabetes Metab Disord 2018; 17:19-30. [PMID: 30288382 PMCID: PMC6154523 DOI: 10.1007/s40200-018-0334-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 01/17/2018] [Indexed: 02/07/2023]
Abstract
The heterogeneity of tumor is considered as a major difficulty to victorious personalized cancer medicine. There is an extremeneed of consistent response evaluation for in vivo tumor heterogeneity anditscoupledconflict mechanisms. In this occasion researchers will be able to keep pace withpredictive, preventive, personalized, and Participatory (P4) medicine for cancer managements. In fact tumor heterogeneity is a central part of cancer evolution,soin order to progress in understanding of the dynamics within a tumor some diagnostic apparatus should be improved. Latest molecular techniques like Next generation Sequencing (NGS) and ultra-deep sequencing could disclose some clones within a liquid tumor biopsy which mainly responsible of treatment resistance. Circulating tumor DNA (ctDNA) as a main component of liquid biopsy is agifted biomarker for cancer mutation tracking as well as profiling. Personalized medicine facilitate learning regarding to genetic pools of tumor and their possible respond to treatment which could be much easier by using of ctDNA.With this information, cliniciansarelooking forward to find the best strategies for prevention, screening, and treatment in the way of precision medicine. Currently, numerous clinical efficacy of such informative improved treatment are in hand. Here we represent the review of plasma-derived ctDNA studies use in personalized cancer managements.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Departments of Pathology, Doctor Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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27
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Gorgannezhad L, Umer M, Islam MN, Nguyen NT, Shiddiky MJA. Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies. LAB ON A CHIP 2018; 18:1174-1196. [PMID: 29569666 DOI: 10.1039/c8lc00100f] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Cell-free DNA (cfDNA) refers to short fragments of acellular nucleic acids detectable in almost all body fluids, including blood, and is involved in various physiological and pathological phenomena such as immunity, coagulation, aging, and cancer. In cancer patients, a fraction of hematogenous cfDNA originates from tumors, termed circulating tumor DNA (ctDNA), and may carry the same mutations and genetic alterations as those of a primary tumor. Thus, ctDNA potentially provides an opportunity for noninvasive assessment of cancer. Recent advances in ctDNA analysis methods will potentially lead to the development of a liquid biopsy tool for the diagnosis, prognosis, therapy response monitoring, and tracking the rise of new mutant sub-clones in cancer patients. Over the past few decades, cancer-specific mutations in ctDNA have been detected using a variety of untargeted methods such as digital karyotyping, personalized analysis of rearranged ends (PARE), whole-genome sequencing of ctDNA, and targeted approaches such as conventional and digital PCR-based methods and deep sequencing-based technologies. More recently, several chip-based electrochemical sensors have been developed for the analysis of ctDNA in patient samples. This paper aims to comprehensively review the diagnostic, prognostic, and predictive potential of ctDNA as a minimally invasive liquid biopsy for cancer patients. We also present an overview of current advances in the analytical sensitivity and accuracy of ctDNA analysis methods as well as biological and technical challenges, which need to be resolved for the integration of ctDNA analysis into routine clinical practice.
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Affiliation(s)
- Lena Gorgannezhad
- School of Environment and Science, Griffith University, Nathan Campus, QLD 4111, Australia. and Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Muhammad Umer
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Md Nazmul Islam
- School of Environment and Science, Griffith University, Nathan Campus, QLD 4111, Australia. and Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Nam-Trung Nguyen
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Muhammad J A Shiddiky
- School of Environment and Science, Griffith University, Nathan Campus, QLD 4111, Australia. and Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
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Hench IB, Hench J, Tolnay M. Liquid Biopsy in Clinical Management of Breast, Lung, and Colorectal Cancer. Front Med (Lausanne) 2018; 5:9. [PMID: 29441349 PMCID: PMC5797586 DOI: 10.3389/fmed.2018.00009] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/15/2018] [Indexed: 12/12/2022] Open
Abstract
Examination of tumor molecular characteristics by liquid biopsy is likely to greatly influence personalized cancer patient management. Analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and tumor-derived exosomes, all collectively referred to as “liquid biopsies,” are not only a modality to monitor treatment efficacy, disease progression, and emerging therapy resistance mechanisms, but they also assess tumor heterogeneity and evolution in real time. We review the literature concerning the examination of ctDNA and CTC in a diagnostic setting, evaluating their prognostic, predictive, and monitoring capabilities. We discuss the advantages and limitations of various leading ctDNA/CTC analysis technologies. Finally, guided by the results of clinical trials, we discuss the readiness of cell-free DNA and CTC as routine biomarkers in the context of various common types of neoplastic disease. At this moment, one cannot conclude whether or not liquid biopsy will become a mainstay in oncology practice.
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Affiliation(s)
- Ivana Bratić Hench
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Jürgen Hench
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Markus Tolnay
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
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29
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Perrone F, Lampis A, Bertan C, Verderio P, Ciniselli CM, Pizzamiglio S, Frattini M, Nucifora M, Molinari F, Gallino G, Gariboldi M, Meroni E, Leo E, Pierotti MA, Pilotti S. Circulating Free DNA in a Screening Program for Early Colorectal Cancer Detection. TUMORI JOURNAL 2018; 100:115-21. [DOI: 10.1177/030089161410000201] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aims and Background The quantification and molecular characterization of circulating free DNA (cfDNA) have attracted much interest as new and promising, noninvasive means of detecting and monitoring the presence of surgical resectable colorectal cancer (CRC). Instead, the role of cfDNA in the early detection of malignant and premalignant colorectal lesions is still unclear. The aim of this study was to evaluate the predictive power of the quantification and KRAS status of cfDNA in detecting early colorectal lesions in plasma from healthy high-risk subjects. Methods The study population consisted of 170 consecutive healthy high-risk subjects aged >50 years who participated in the screening program promoted by the Local Health Service (ASL-Milano) for early CRC detection and who underwent endoscopic examination after being found positive at fecal occult blood test (FOBT). Thirty-four participants had malignant lesions consisting of 12 adenocarcinomas (at an early stage in half of the cases) and 22 instances of high-grade intraepithelial neoplasia (HGIN) in adenomas; 73 participants had premalignant lesions (adenomas and hyperplasia), and 63 participants had no lesions. Plasma cfDNA was quantified by quantitative real-time PCR and analyzed for KRAS mutations by a mutant-enriched PCR. KRAS status was assessed also in matched adenocarcinoma and HGIN tissues. The distribution of cfDNA concentrations among FOBT-positive subjects with diagnosed lesion (cases) was compared with that of FOBT-positive subjects without lesions (controls) and its predictive capability (AUC) was assessed. Results The predictive capability of cfDNA levels was satisfactory in predicting adenocarcinomas (AUC 0.709; 95% CI, 0.508–0.909) but not HGIN and premalignant lesions. The rate of KRAS mutations in plasma was low (5/170 = 3%) compared with the rate observed in the matched adenocarcinoma and HGIN tissues (45%). Conclusions The use of cfDNA quantification to predict adenocarcinoma at an early stage in high-risk (aged >50 years and FOBT positive) subjects seems to be promising but needs more sensitive methods to improve cfDNA detection.
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Affiliation(s)
- Federica Perrone
- Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Lampis
- Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Claudia Bertan
- Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Verderio
- Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara M Ciniselli
- Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pizzamiglio
- Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Milo Frattini
- Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Martina Nucifora
- Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Molinari
- Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Gianfranco Gallino
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Manuela Gariboldi
- Division of Diagnostic Endoscopy and Endoscopic Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Emanuele Meroni
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ermanno Leo
- Laboratory of Molecular Diagnostics, Institute of Pathology, Locarno, Switzerland
| | - Marco A Pierotti
- Molecular Genetics of Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
- Division of Diagnostic Endoscopy and Endoscopic Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvana Pilotti
- Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Agah S, Akbari A, Talebi A, Masoudi M, Sarveazad A, Mirzaei A, Nazmi F. Quantification of Plasma Cell-Free Circulating DNA at Different Stages of Colorectal Cancer. Cancer Invest 2017; 35:625-632. [DOI: 10.1080/07357907.2017.1408814] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Masoudi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Arash Sarveazad
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Mirzaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Farinaz Nazmi
- Department of Zoology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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31
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Miyamoto Y, Zhang W, Lenz HJ. Molecular Landscape and Treatment Options for Patients with Metastatic Colorectal Cancer. Indian J Surg Oncol 2017; 8:580-590. [PMID: 29203992 PMCID: PMC5705494 DOI: 10.1007/s13193-016-0543-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 07/14/2016] [Indexed: 12/13/2022] Open
Abstract
Over the last 20 years, median survival for patients with metastatic colorectal cancer (CRC) has remarkably improved from about 12 to over 30 months, mainly because of the development of new agents and patient selection using predictive biomarkers. However, the identification of the most effective treatment for an individual patient is still a challenge. Molecular profiling of CRC has made great progress, but it is limited by tumor heterogeneity and absence of driver mutation. However, RAS, BRAF, and microsatellite instability are validated biomarker recommended by NCCN and ESMO. In this review, we discuss recent advances and future developments.
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Affiliation(s)
- Yuji Miyamoto
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
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Fleshner P, Braunstein GD, Ovsepyan G, Tonozzi TR, Kammesheidt A. Tumor-associated DNA mutation detection in individuals undergoing colonoscopy. Cancer Med 2017; 7:167-174. [PMID: 29125240 PMCID: PMC5773968 DOI: 10.1002/cam4.1249] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 10/06/2017] [Accepted: 10/08/2017] [Indexed: 02/06/2023] Open
Abstract
The majority of colorectal cancers (CRC) harbor somatic mutations and epigenetic modifications in the tumor tissue, and some of these mutations can be detected in plasma as circulating tumor DNA (ctDNA). Precancerous colorectal lesions also contain many of these same mutations. This study examined plasma for ctDNA from patients undergoing a screening or diagnostic colonoscopy to determine the sensitivity and specificity of the ctDNA panel for detecting CRC and precancerous lesions. Two hundred patients without a history of nonskin cancer had blood drawn before a colonoscopy. Plasma ctDNA was measured with a 96 mutation panel for nine cancer driver genes. The ctDNA results were correlated with the findings at colonoscopy. Of the 200 patients, 176 (88%) had wild‐type DNA, 12 (6%) had mutations detected, and 12 (6%) had indeterminate results. Colonoscopy was normal in 80% of the patients and 20% were found to have polyps. No CRC was found in this study, precluding a determination of true‐positive rate for CRC detection. Our ctDNA panel was positive in 13.2% of patients with colonic polyps found at colonoscopy, while 4.7% of patients with normal colonoscopy also had ctDNA detected, which may represent ctDNA released from a benign process, an occult tumor, or an acquired somatic mutation from clonal hematopoiesis.
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Affiliation(s)
- Phillip Fleshner
- Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, 90048
| | | | - Gayane Ovsepyan
- Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, 90048
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Variations in transrenal DNA and comparison with plasma DNA as a diagnostic marker for colorectal cancer. Int J Biol Markers 2017; 32:e434-e440. [PMID: 28708207 DOI: 10.5301/ijbm.5000288] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Transrenal DNA can potentially be useful in the disease management of colorectal cancer (CRC) and has potential diagnostic utility. Our study aimed to conduct preoperative and postoperative analysis of KRAS-positive patients, using transrenal DNA compared with plasma DNA. This is critically needed for disease diagnostics and treatment response monitoring. METHODS CRC patients at different stages of the disease and with different molecular profiles were recruited for serial time-point analysis. Preoperative and postoperative urine specimens were extracted and compared with tumor tissues and plasma DNA. RESULTS Our analysis demonstrated that transrenal DNA offered comparable sensitivity and specificity to plasma DNA analysis. Collection of transrenal DNA, being noninvasive, is an attractive assay and easily allows serial monitoring of the disease. Results from preoperative detection showed a close correlation to tumor tissue profiling and demonstrated close associations to the disease. We also observed significant decreases in mutant KRAS DNA concentration after surgery, which confirmed transrenal DNA's sensitivity to treatment response. CONCLUSIONS The use of transrenal DNA offers a possible alternative method of disease profiling, detection and tracking. Our study is one of the first to systematically analyze a relatively large number of different CRC patients using transrenal DNA. The positive correlation with disease demonstrates the assay's viability in the clinical setting, and our method further opens up the possibility to use transrenal DNA for clinical intervention investigations.
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Colorectal Cancer Blood-Based Biomarkers. Gastroenterol Res Pract 2017; 2017:2195361. [PMID: 29147109 PMCID: PMC5632863 DOI: 10.1155/2017/2195361] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/16/2017] [Accepted: 09/13/2017] [Indexed: 12/26/2022] Open
Abstract
Mortality and morbidity associated with colorectal cancer (CRC) are increasing globally, partly due to lack of early detection of the disease. The screening is usually performed with colonoscopy, which is invasive and unpleasant, discouraging participation in the screening. As a source of noninvasive and easily accessible biomarkers, liquid biopsies are emerging. Blood-based biomarkers have the potential as diagnostic and prognostic tool in CRC. Early stage detection of CRC with high sensitivity and specificity would likely lead to higher participation in the screening test. It would also improve the prognosis of the disease and improve the recurrence risk. In this review, we summarize the potential biomarkers for early detection and monitoring of CRC.
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伍 婧, 招 丽, 林 秀, 冯 芬, 陈 永, 邓 伟, 邓 燕, 王 巍. [Association of RAS mutations in circulating cell-free DNA in the plasma with clinicopathological features of colorectal cancer]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:962-966. [PMID: 28736377 PMCID: PMC6765521 DOI: 10.3969/j.issn.1673-4254.2017.07.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To detect RAS mutations in the circulating cell-free DNA (cfDNA) in the plasma and explore the their correlation with the clinicopathological features in patients with colorectal cancer. METHODS Real-time PCR was used to detect RAS mutations in plasma cfDNA and matched tumor tissue DNA samples from 71 colorectal cancer patients. The correlation of RAS mutations with the clinicopathological features of the patients were analyzed. RESULTS Of the 71 patients with colorectal cancer, 23 (32.39%) showed RAS mutations in the cfDNA and 36 (50.7%) showed RAS mutations in tumor tissue DNA, with a concordance rate of 76.06% in the results between the two samples (Kappa=0.523). RAS mutations in the cfDNA were not related to the patients' age (P=0.072), gender (P=0.320), tumor stage (IVa and IVb, P=0.450), primary tumor position (P=0.324), lung metastasis (P=0.237), CEA level (P=0.284) or CA199 level (P=0.427). The positivity rate of RAS mutations in plasma cfDNA was significantly higher in patients with liver metastasis than those without liver metastasis (P=0.045). CONCLUSION Plasma cfDNA can be a reliable source of diagnostic DNA to replace the tumor tissue DNA for diagnosis of RAS mutations. RAS mutations in plasma cfDNA occur more frequently in colorectal cancer patients with liver metastasis.
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Affiliation(s)
- 婧 伍
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 丽蓉 招
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 秀强 林
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 芬 冯
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 永昌 陈
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 伟英 邓
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 燕明 邓
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
| | - 巍 王
- />佛山市第一人民医院肿瘤中心胃肠肿瘤内科，广东 佛山 528000Department of Gastrointestinal Oncology, First People's Hospital of Foshan, Foshan 528000, China
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Howell JA, Khan SA, Knapp S, Thursz MR, Sharma R. The clinical role of circulating free tumor DNA in gastrointestinal malignancy. Transl Res 2017; 183:137-154. [PMID: 28056336 DOI: 10.1016/j.trsl.2016.12.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 10/14/2016] [Accepted: 12/06/2016] [Indexed: 02/06/2023]
Abstract
Circulating cell-free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor-derived circulating cell-free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated "liquid biopsy" of cancer, facilitating real-time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies.
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Affiliation(s)
- Jessica A Howell
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK; Centre for Population Health, MacFarlane-Burnet Institute, Melbourne, Australia; Department of Medicine, The University of Melbourne, Melbourne, Australia.
| | - Shahid A Khan
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Susanne Knapp
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Mark R Thursz
- Department of Hepatology, St Mary's Hospital, Imperial College, London, UK
| | - Rohini Sharma
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College, London, UK
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Corrò C, Hejhal T, Poyet C, Sulser T, Hermanns T, Winder T, Prager G, Wild PJ, Frew I, Moch H, Rechsteiner M. Detecting circulating tumor DNA in renal cancer: An open challenge. Exp Mol Pathol 2017; 102:255-261. [PMID: 28214514 DOI: 10.1016/j.yexmp.2017.02.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 02/11/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Detection of circulating tumor DNA (ctDNA) in blood of cancer patients is regarded as an important step towards personalized medicine and treatment monitoring. In the present study, we investigated the clinical applicability of ctDNA as liquid biopsy in renal cancer. METHODS ctDNA in serum and plasma samples derived from ccRCC and colon cancer patients as well as ctDNA isolated from RCC xenografts with known VHL mutation status was investigated using next generation sequencing (NGS). Additionally, a Taqman mutation specific assay was used for specific VHL mutation detection in blood. RESULTS In our study, we successfully identified KRAS mutation in colon cancer patients. We also confirmed the presence of specific VHL mutations in ctDNA derived from RCC xenografts indicating the capability of renal tumors to release DNA into the blood circulation. However, we could not detect any VHL mutation in plasma or serum samples derived from nine ccRCC patients. To increase the sensitivity, a VHL mutation specific Taqman assay was tested. With this approach, the pVHL mutation p.Val130Leu in exon 2 in one patient was successfully detected. CONCLUSION These data suggest a reduced tumor DNA shedding and an increased clearance of the tumor DNA from the circulation in renal cancer patients independently of tumor size, metastases, and necrosis. This implies that highly sensitive detection methods for mutation calling and prior knowledge of the mutation are required for liquid biopsies in ccRCC.
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Affiliation(s)
- Claudia Corrò
- Institute of Surgical Pathology, University Hospital Zurich, Switzerland
| | - Tomas Hejhal
- Institute of Physiology, University of Zurich, Switzerland
| | - Cédric Poyet
- Department of Urology, University Hospital Zurich, Switzerland
| | - Tullio Sulser
- Department of Urology, University Hospital Zurich, Switzerland
| | - Thomas Hermanns
- Department of Urology, University Hospital Zurich, Switzerland
| | - Thomas Winder
- Department of Oncology, University Hospital Zurich, Switzerland
| | - Gerald Prager
- Department of Oncology, University Hospital Vienna, Austria
| | - Peter J Wild
- Institute of Surgical Pathology, University Hospital Zurich, Switzerland
| | - Ian Frew
- Institute of Physiology, University of Zurich, Switzerland
| | - Holger Moch
- Institute of Surgical Pathology, University Hospital Zurich, Switzerland
| | - Markus Rechsteiner
- Institute of Surgical Pathology, University Hospital Zurich, Switzerland.
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Camus V, Miloudi H, Taly A, Sola B, Jardin F. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. J Hematol Oncol 2017; 10:47. [PMID: 28196522 PMCID: PMC5307790 DOI: 10.1186/s13045-017-0412-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/31/2017] [Indexed: 02/07/2023] Open
Abstract
Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin's lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.
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Affiliation(s)
- Vincent Camus
- Normandie Univ, INSERM U1245, UNICAEN, UNIROUEN, Caen, France
- Department of Hematology, Centre Henri Becquerel, Rouen, France
| | - Hadjer Miloudi
- Normandie Univ, INSERM U1245, UNICAEN, UNIROUEN, Caen, France
| | - Antoine Taly
- Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, CNRS, Université Paris Diderot, Paris, France
| | - Brigitte Sola
- Normandie Univ, INSERM U1245, UNICAEN, UNIROUEN, Caen, France.
| | - Fabrice Jardin
- Normandie Univ, INSERM U1245, UNICAEN, UNIROUEN, Caen, France
- Department of Hematology, Centre Henri Becquerel, Rouen, France
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Perakis S, Auer M, Belic J, Heitzer E. Advances in Circulating Tumor DNA Analysis. Adv Clin Chem 2017; 80:73-153. [PMID: 28431643 DOI: 10.1016/bs.acc.2016.11.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The analysis of cell-free circulating tumor DNA (ctDNA) is a very promising tool and might revolutionize cancer care with respect to early detection, identification of minimal residual disease, assessment of treatment response, and monitoring tumor evolution. ctDNA analysis, often referred to as "liquid biopsy" offers what tissue biopsies cannot-a continuous monitoring of tumor-specific changes during the entire course of the disease. Owing to technological improvements, efforts for the establishment of preanalytical and analytical benchmark, and the inclusion of ctDNA analyses in clinical trial, an actual clinical implementation has come within easy reach. In this chapter, recent advances of the analysis of ctDNA are summarized starting from the discovery of cell-free DNA, to methodological approaches and the clinical applicability.
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Affiliation(s)
- Samantha Perakis
- Institute of Human Genetics, Medical University of Graz, Graz, Austria
| | - Martina Auer
- Institute of Human Genetics, Medical University of Graz, Graz, Austria
| | - Jelena Belic
- Institute of Human Genetics, Medical University of Graz, Graz, Austria
| | - Ellen Heitzer
- Institute of Human Genetics, Medical University of Graz, Graz, Austria.
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Suraj S, Dhar C, Srivastava S. Circulating nucleic acids: An analysis of their occurrence in malignancies. Biomed Rep 2016; 6:8-14. [PMID: 28123700 DOI: 10.3892/br.2016.812] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/15/2016] [Indexed: 12/18/2022] Open
Abstract
Through a regulated or fortuitous phenomenon, small portions of cell nucleic acids are thrown into circulation. Since the discovery of these circulating nucleic acids (CNAs) in 1948, numerous studies have been published to elucidate their clinical implications in multifarious diseases. Scientists have now discovered disease-specific genetic aberrations, such as mutations, microsatellite alterations, epigenetic modulations (including aberrant methylation), as well as viral DNA/RNA from nucleic acids in plasma and serum. CNAs have become increasingly popular due to their potential for use as a liquid biopsy, which is a tool for non-invasive diagnosis and monitoring of diseases, such as cancer, stroke, trauma, myocardial infarction, autoimmune disorders, and pregnancy-associated complications. While the diagnostic potential of CNAs has been investigated extensively, there is a paucity of understanding of their pathophysiological functions. Are these CNAs part of the cell's regular framework of functioning? Or do they act as molecular players in disease initiation and progression? The aim of this review is to investigate the origins and functions of the circulating cell-free nucleic acids in the plasma and serum of patients with various malignancies, and propose areas of study, which may elucidate the novel underlying mechanisms that are functioning during cancer initiation/progression.
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Affiliation(s)
- Shankar Suraj
- Department of Transfusion Medicine and Immunohematology, St. John's Medical College and Hospital, St. John's National Academy of Health Sciences, Bangalore, Karnataka 560034, India
| | - Chirag Dhar
- St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, Karnataka 560034, India
| | - Sweta Srivastava
- Department of Transfusion Medicine and Immunohematology, St. John's Medical College and Hospital, St. John's National Academy of Health Sciences, Bangalore, Karnataka 560034, India
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Camus V, Sarafan-Vasseur N, Bohers E, Dubois S, Mareschal S, Bertrand P, Viailly PJ, Ruminy P, Maingonnat C, Lemasle E, Stamatoullas A, Picquenot JM, Cornic M, Beaussire L, Bastard C, Frebourg T, Tilly H, Jardin F. Digital PCR for quantification of recurrent and potentially actionable somatic mutations in circulating free DNA from patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2016; 57:2171-9. [PMID: 26883583 DOI: 10.3109/10428194.2016.1139703] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy harboring frequent targetable activating somatic mutations. Emerging evidence suggests that circulating cell-free DNA (cfDNA) can be used to detect somatic variants in DLBCL using Next-Generation Sequencing (NGS) experiments. In this proof-of-concept study, we chose to develop simple and valuable digital PCR (dPCR) assays for the detection of recurrent exportin-1 (XPO1) E571K, EZH2 Y641N, and MYD88 L265P mutations in DLBCL patients, thereby identifying patients most likely to potentially benefit from targeted therapies. We demonstrated that our dPCR assays were sufficiently sensitive to detect rare XPO1, EZH2, and MYD88 mutations in plasma cfDNA, with a sensitivity of 0.05%. cfDNA somatic mutation detection by dPCR seems to be a promising technique in the management of DLBCL, in addition to NGS experiments.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biomarkers, Tumor
- DNA, Neoplasm/blood
- DNA, Neoplasm/genetics
- Female
- High-Throughput Nucleotide Sequencing/methods
- Humans
- Karyopherins/genetics
- Liquid Biopsy
- Lymphoma, Large B-Cell, Diffuse/diagnostic imaging
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Middle Aged
- Mutation
- Myeloid Differentiation Factor 88/genetics
- Neoplasm Staging
- Positron-Emission Tomography
- Real-Time Polymerase Chain Reaction
- Receptors, Cytoplasmic and Nuclear/genetics
- Recurrence
- Exportin 1 Protein
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Affiliation(s)
- Vincent Camus
- a Department of Hematology , Centre Henri Becquerel , Rouen , France
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | | | - Elodie Bohers
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | - Sydney Dubois
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | - Sylvain Mareschal
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | - Philippe Bertrand
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | | | - Philippe Ruminy
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | | | - Emilie Lemasle
- a Department of Hematology , Centre Henri Becquerel , Rouen , France
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | - Aspasia Stamatoullas
- a Department of Hematology , Centre Henri Becquerel , Rouen , France
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | | | - Marie Cornic
- d Department of Pathology , Centre Henri Becquerel , Rouen , France
| | | | - Christian Bastard
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
- e Department of Genetic Oncology , Centre Henri Becquerel , Rouen , France
| | | | - Hervé Tilly
- a Department of Hematology , Centre Henri Becquerel , Rouen , France
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
| | - Fabrice Jardin
- a Department of Hematology , Centre Henri Becquerel , Rouen , France
- b INSERM U918, Centre Henri Becquerel, University of Rouen , Rouen , France
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Qian C, Ju S, Qi J, Zhao J, Shen X, Jing R, Yu J, Li L, Shi Y, Zhang L, Wang Z, Cong H. Alu-based cell-free DNA: a novel biomarker for screening of gastric cancer. Oncotarget 2016; 8:54037-54045. [PMID: 28903321 PMCID: PMC5589560 DOI: 10.18632/oncotarget.11079] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 07/18/2016] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer and the second major cause of cancer-related deaths worldwide. In our previous study, a novel and sensitive method for quantifying cell-free DNA (CFD) in human blood was established and tested for its ability to predict patients with tumor. We want to investigate CFD expression in the sera of GC patients in an attempt to explore the clinical significance of CFD in improving the early screening of GC and monitoring GC progression by the branched DNA (bDNA)-based Alu assay. The concentration of CFD was quantitated by bDNA-based Alu assay. CEA, CA19-9, C72-4 and CA50 concentrations were determined by ABBOTT ARCHITECT I2000 SR. We found the CFD concentrations have significant differences between GC patients, benign gastric disease (BGD) patients and healthy controls (P < 0.05). CFD were weakly correlated with CEA (r = −0.197, P < 0.05) or CA50 (r = 0.206, P < 0.05), and no correlation with CA19-9 (r = −0.061, P > 0.05) or CA72-4 (r = 0.011, P > 0.05). In addition, CFD concentrations were significantly higher in stage I GC patients than BGD patients and healthy controls (P < 0.05), but there was no significant difference in CEA, CA19-9 and CA50 among the three traditional tumor markers (P > 0.05). Our analysis showed that CFD was more sensitive than CEA, CA19-9, CA72-4 or CA50 in early screening of GC. Compared with CEA, CA19-9, CA72-4 and CA50, CFD may prove to be a better biomarker for the screening of GC, thus providing a sensitive biomarker for screening and monitoring progression of GC.
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Affiliation(s)
- Chen Qian
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.,Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Jing Qi
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Jianmei Zhao
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Xianjuan Shen
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Rongrong Jing
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Juan Yu
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Li Li
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Yingjuan Shi
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Lurong Zhang
- Department of Radiation Oncology, UF Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA
| | - Zhiwei Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Hui Cong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
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Abstract
Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134–144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132–145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA. During cell death, DNA that is not contained within a membrane (i.e., cell-free DNA) enters the circulation. Detecting cell-free DNA originating from solid tumors (i.e., circulating tumor DNA, ctDNA), particularly solid tumors that have not metastasized, has proven challenging due to the relatively abundant background of normally occurring cell-free DNA derived from healthy cells. Our study defines the subtle but distinct differences in fragment length between normal cell-free DNA and ctDNA from a variety of solid tumors. Specifically, ctDNA was overall consistently shorter than the fragment length of normal cell-free DNA. Subsequently, we showed that a size-selection for shorter cell-free DNA fragments increased the proportion of ctDNA within a sample. These results provide compelling evidence that development of techniques to isolate a subset of cell-free DNA consistent with the ctDNA fragment lengths described in our study may substantially improve detection of non-metastatic solid tumors. As such, our findings may have a direct impact on the clinical utility of ctDNA for the non-invasive detection and diagnosis of solid tumors (i.e., the “liquid biopsy”), monitoring tumor recurrence, and evaluating tumor response to therapy.
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Aghagolzadeh P, Radpour R. New trends in molecular and cellular biomarker discovery for colorectal cancer. World J Gastroenterol 2016; 22:5678-5693. [PMID: 27433083 PMCID: PMC4932205 DOI: 10.3748/wjg.v22.i25.5678] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/16/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, which is consequence of multistep tumorigenesis of several genetic and epigenetic events. Since CRC is mostly asymptomatic until it progresses to advanced stages, the early detection using effective screening approaches, selection of appropriate therapeutic strategies and efficient follow-up programs are essential to reduce CRC mortalities. Biomarker discovery for CRC based on the personalized genotype and clinical information could facilitate the classification of patients with certain types and stages of cancer to tailor preventive and therapeutic approaches. These cancer-related biomarkers should be highly sensitive and specific in a wide range of specimen(s) (including tumor tissues, patients’ fluids or stool). Reliable biomarkers which enable the early detection of CRC, can improve early diagnosis, prognosis, treatment response prediction, and recurrence risk. Advances in our understanding of the natural history of CRC have led to the development of different CRC associated molecular and cellular biomarkers. This review highlights the new trends and approaches in CRC biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches and follow-up of patients.
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Tan CRC, Zhou L, El-Deiry WS. Circulating Tumor Cells Versus Circulating Tumor DNA in Colorectal Cancer: Pros and Cons. CURRENT COLORECTAL CANCER REPORTS 2016; 12:151-161. [PMID: 27516729 DOI: 10.1007/s11888-016-0320-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are emerging noninvasive multifunctional biomarkers in liquid biopsy allowing for early diagnosis, accurate prognosis, therapeutic target selection, spatiotemporal monitoring of metastasis, as well as monitoring response and resistance to treatment. CTCs and ctDNA are released from different tumor types at different stages and contribute complementary information for clinical decision. Although big strides have been taken in technology development for detection, isolation and characterization of CTCs and sensitive and specific detection of ctDNA, CTC-, and ctDNA-based liquid biopsies may not be widely adopted for routine cancer patient care until the suitability, accuracy, and reliability of these tests are validated and more standardized protocols are corroborated in large, independent, prospectively designed trials. This review covers CTC- and ctDNA-related technologies and their application in colorectal cancer. The promise of CTC-and ctDNA-based liquid biopsies is envisioned.
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Affiliation(s)
- Carlyn Rose C Tan
- Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Lanlan Zhou
- Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Wafik S El-Deiry
- Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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Lin D, Huang H, Qiu S, Feng S, Chen G, Chen R. Diagnostic potential of polarized surface enhanced Raman spectroscopy technology for colorectal cancer detection. OPTICS EXPRESS 2016; 24:2222-34. [PMID: 26906798 DOI: 10.1364/oe.24.002222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
The purpose of this study was to develop a more powerful blood analysis method based on polarized surface enhanced Raman spectroscopy (SERS) technology for non-invasive and sensitive colorectal cancer (CRC) detection. The efficiency of different polarized scattering signals (non-polarization, parallel polarization and perpendicular polarization) on blood serum SERS was explored for the first time. Results demonstrated that polarized SERS was more sensitive to explore distinctive spectral differences between cancer and normal groups. And higher diagnostic accuracy of 91.6% could be achieved using polarized SERS integrated with PCA-LDA for classification of the two serum groups in comparison to conventional SERS technology. This exploratory study demonstrated that the nanobiosensor based on polarized SERS technique in conjunction with PCA-LDA provided a novel strategy for blood SERS analysis, and had the potential as a clinical complement for CRC screening.
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Yörüker EE, Holdenrieder S, Gezer U. Blood-based biomarkers for diagnosis, prognosis and treatment of colorectal cancer. Clin Chim Acta 2016; 455:26-32. [PMID: 26797671 DOI: 10.1016/j.cca.2016.01.016] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/15/2016] [Accepted: 01/16/2016] [Indexed: 02/07/2023]
Abstract
The global burden of colorectal cancer (CRC)-associated morbidity and mortality is increasing, in part due to a lack of early detection. Direct structural examination techniques, such as colonoscopy, are invasive and can therefore affect the willingness of patients to participate in screening. Recently, the use of "liquid biopsy" has gained considerable attention as a novel source of biomarkers. Blood-based biomarkers could prove to be practical tools for CRC detection, as the monitoring of biomarkers in biological fluids offers many advantages, including minimal invasiveness and easy accessibility. Biomarkers with high specificity and sensitivity can enable the detection of CRC at an early stage, thereby improving prognosis, prediction of treatment response, and recurrence risk. In this review, we summarize that the biomarkers currently thought to have potential for the early detection and monitoring of CRC, including circulating tumor cells, DNA, RNA and proteins.
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Affiliation(s)
- Ebru E Yörüker
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey.
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Majer W, Kluzek K, Bluyssen H, Wesoły J. Potential Approaches and Recent Advances in Biomarker Discovery in Clear-Cell Renal Cell Carcinoma. J Cancer 2015; 6:1105-13. [PMID: 26516358 PMCID: PMC4615346 DOI: 10.7150/jca.12145] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 06/12/2015] [Indexed: 02/06/2023] Open
Abstract
The early diagnosis and monitoring of clear-cell Renal Cell Carcinoma (ccRCC), which is the most common renal malignancy, remains challenging. The late diagnosis and lack of tools that can be used to assess the progression of the disease and metastasis significantly influence the chance of survival of ccRCC patients. Molecular biomarkers have been shown to aid the diagnosis and disease monitoring for other cancers, but such markers are not currently available for ccRCC. Recently, plasma and serum circulating nucleic acids, nucleic acids present in urine, and plasma and urine proteins gained interest in the field of cancer biomarker discovery. Here, we describe the applicability of plasma and urine nucleic acids as cancer biomarkers with a particular focus on DNA, small RNA, and protein markers for ccRCC.
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Affiliation(s)
- Weronika Majer
- 1. Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, University of Adam Mickiewicz, Umultowska 89, 61-614 Poznan, Poland, Tel. +4861 829 5832, Fax. +4861 829 5949
| | - Katarzyna Kluzek
- 2. Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, University of Adam Mickiewicz, Umultowska 89, 64-614 Poznan, Tel. +4861 829 5832
| | - Hans Bluyssen
- 2. Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, University of Adam Mickiewicz, Umultowska 89, 64-614 Poznan, Tel. +4861 829 5832
| | - Joanna Wesoły
- 1. Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, University of Adam Mickiewicz, Umultowska 89, 61-614 Poznan, Poland, Tel. +4861 829 5832, Fax. +4861 829 5949
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Tabernero J, Lenz HJ, Siena S, Sobrero A, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Yoshino T, Goldberg RM, Sargent DJ, Wagner A, Laurent D, Teufel M, Jeffers M, Grothey A, Van Cutsem E. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol 2015; 16:937-48. [PMID: 26184520 DOI: 10.1016/s1470-2045(15)00138-2] [Citation(s) in RCA: 261] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 04/29/2015] [Accepted: 04/30/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. METHODS We used BEAMing technology to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest-angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor-in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. FINDINGS Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS (KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA (PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35-0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40-0·65 for KRAS mutant [KRAS wild type vs mutant, pinteraction=0·74]; HR 0·50, 95% CI 0·40-0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32-0·89 for PIK3CA mutant [PIK3CA wild-type vs mutant, pinteraction=0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40-0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40-0·70, for high circulating DNA concentrations; low vs high circulating DNA, pinteraction=0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. INTERPRETATION BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. FUNDING Bayer HealthCare Pharmaceuticals.
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Affiliation(s)
- Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Heinz-Josef Lenz
- University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA
| | - Salvatore Siena
- Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Università di Milano, Milan, Italy
| | | | | | | | - Yves Humblet
- St-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - Olivier Bouché
- Centre Hospitalier Universitaire Reims, Robert Debré Hospital, Reims, France
| | - Laurent Mineur
- Gastrointestinal and Liver Oncology Unit, Institut Sainte Catherine, Avignon, France
| | - Carlo Barone
- Catholic University of Sacred Heart, Rome, Italy
| | | | | | - Richard M Goldberg
- Ohio State University School of Medicine, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | | | | | | | | | | | | | - Eric Van Cutsem
- University Hospital Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium
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Hao TB, Shi W, Shen XJ, Qi J, Wu XH, Wu Y, Tang YY, Ju SQ. Circulating cell-free DNA in serum as a biomarker for diagnosis and prognostic prediction of colorectal cancer. Br J Cancer 2014; 111:1482-9. [PMID: 25157833 PMCID: PMC4200099 DOI: 10.1038/bjc.2014.470] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 07/07/2014] [Accepted: 07/16/2014] [Indexed: 12/15/2022] Open
Abstract
Background: To verify whether the concentrations and integrity index of circulating cell-free DNA (ccf-DNA) in serum may be clinically useful for the diagnosis and progression monitoring of colorectal cancer (CRC) patients. Methods: Serum samples were collected from 104 with primary CRC, 85 with operated CRC, 16 with recurrent/metastatic CRC, 63 patients with intestinal polyps and 110 normal controls. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats (ALU-qPCR). Serum carcinoembryonic antigen (CEA) level was detected by ARCHITECT assay. Results: The median absolute serum ALU115 and ALU247/115 in primary CRC group was significantly higher than those in intestinal polyp and normal control groups (both P<0.0001), in recurrent/metastatic CRC was significantly higher compared with primary CRC (P=0.0021, P=0.0018) or operated CRC (P<0.0001, respectively) and during follow-up, ALU115 and ALU247/115 were increased before surgery and decreased significantly after surgery. Conclusions: Combined detection of ALU115, ALU247/115 and CEA could improve the diagnostic efficiency for CRC. Serum DNA concentrations and integrity index may be valuable in early complementary diagnosis and monitoring of progression and prognosis of CRC.
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Affiliation(s)
- T B Hao
- Medical School of Nantong University, Nantong 226000, Jiangsu Province, China
| | - W Shi
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - X J Shen
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - J Qi
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - X H Wu
- Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China
| | - Y Wu
- Medical School of Nantong University, Nantong 226000, Jiangsu Province, China
| | - Y Y Tang
- Medical School of Nantong University, Nantong 226000, Jiangsu Province, China
| | - S Q Ju
- 1] Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong 226000, Jiangsu Province, China [2] Center of Laboratory Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong 226000, Jiangsu Province, China
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