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Li B, Yim MM, Jin YX, Tao BK, Xie JS, Balas M, Khan H, Lam WC, Yan P, Navajas EV. Circulating Cell-Free DNA as an Epigenetic Biomarker for Early Diabetic Retinopathy: A Narrative Review. Diagnostics (Basel) 2025; 15:1161. [PMID: 40361979 PMCID: PMC12071738 DOI: 10.3390/diagnostics15091161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Diabetic retinopathy (DR), a complication of type 2 diabetes mellitus (T2DM), is typically asymptomatic in its early stages. Diagnosis typically relies on routine fundoscopy for the clinical detection of microvascular abnormalities. However, permanent retinal damage may occur well before clinical signs are appreciable. In the early stages of DR, the retina undergoes distinct epigenetic changes, including DNA methylation and histone modifications. Recent evidence supports unique epigenetic 'signatures' in patients with DR compared to non-diabetic controls. These DNA 'signature' sequences may be specific to the retina and may circulate in peripheral blood in the form of cell-free DNA (cfDNA). In this review, we explore the literature and clinical application of cfDNA sampling as an early, non-invasive, accessible assessment tool for early DR detection. First, we summarize the known epigenetic signatures of DR. Next, we review current sequencing technologies used for cfDNA detection, such as magnetic bead-based enrichment, next-generation sequencing, and bisulfite sequencing. Finally, we outline the current research limitations and emerging areas of study which aim to improve the clinical utility of cfDNA for DR evaluation.
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Affiliation(s)
- Boaz Li
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Megan M. Yim
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Yu Xuan Jin
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Brendan K. Tao
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Jim S. Xie
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Michael Balas
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Haaris Khan
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
| | - Wai-Ching Lam
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
| | - Peng Yan
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Eduardo V. Navajas
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
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Esposito G, D’Angelo G, De Falco L, Evangelista E, Savarese G, Fico A, Cinque F, Giampaolino P, Di Spiezio Sardo A, Bifulco G, Della Corte L. The Application of Liquid Biopsy for the Development and Validation of a Non-Invasive Screening and Diagnosis Test for Endometrial Premalignant and Malignant Lesions: A Prospective Innovative Pilot Study. Cancers (Basel) 2025; 17:1078. [PMID: 40227624 PMCID: PMC11988008 DOI: 10.3390/cancers17071078] [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: 01/15/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Background/Objectives: Endometrial cancer (EC) is a common malignancy in developed countries, with incidence closely linked to lifestyle factors and genetic predispositions, notably Lynch syndrome. Traditional biopsy methods for diagnosis and monitoring are invasive. This study aims to develop and validate a non-invasive diagnostic method for EC using liquid biopsy, specifically examining circulating tumor DNA (ctDNA) for its potential in early detection and disease monitoring. Methods: A cohort of 63 patients with EC or atypical endometrial hyperplasia (AEH) was recruited from the Gynecological Unit of the Azienda Ospedaliera Universitaria Federico II. Plasma samples were processed to extract ctDNA, which was sequenced and analyzed for mutations. Matched tumor tissue and germline DNA were also examined to confirm mutation concordance and assess potential genetic predispositions. Results: Pathogenic mutations were identified in plasma ctDNA in 59 out of 63 cases (93%), with a 65% concordance between plasma ctDNA mutations and those found in solid tumor samples. Key mutations in genes such as PTEN, PIK3R1, and KMT2C were significantly associated with a higher tumor grade and advanced stage disease, such as myometrial infiltration. Conclusions: Liquid biopsy shows promise as a minimally invasive diagnostic and monitoring tool for EC, offering real-time insights into tumor biology. The high mutation concordance between the plasma ctDNA and tumor tissue underscores the potential of a liquid biopsy in managing EC, particularly for patients at risk of recurrence. Further longitudinal studies are needed to establish ctDNA as a standard tool in EC diagnosis and monitoring.
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Affiliation(s)
- Giuseppina Esposito
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Giuseppe D’Angelo
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Luigia De Falco
- AMES, Polidiagnostic Strumental Centre, Srl, 80013 Naples, Italy; (L.D.F.); (E.E.); (G.S.); (A.F.)
- Fondazione Genetica per la Vita Onlus, 80132 Naples, Italy
| | - Eloisa Evangelista
- AMES, Polidiagnostic Strumental Centre, Srl, 80013 Naples, Italy; (L.D.F.); (E.E.); (G.S.); (A.F.)
- Fondazione Genetica per la Vita Onlus, 80132 Naples, Italy
| | - Giovanni Savarese
- AMES, Polidiagnostic Strumental Centre, Srl, 80013 Naples, Italy; (L.D.F.); (E.E.); (G.S.); (A.F.)
- Fondazione Genetica per la Vita Onlus, 80132 Naples, Italy
| | - Antonio Fico
- AMES, Polidiagnostic Strumental Centre, Srl, 80013 Naples, Italy; (L.D.F.); (E.E.); (G.S.); (A.F.)
- Fondazione Genetica per la Vita Onlus, 80132 Naples, Italy
| | - Federica Cinque
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Pierluigi Giampaolino
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Attilio Di Spiezio Sardo
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Giuseppe Bifulco
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (G.E.); (F.C.); (P.G.); (A.D.S.S.); (G.B.)
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
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Popescu I, Croitoru VM, Croitoru-Cazacu IM, Dudau AM, Herlea V, Dima SO, Croitoru AE. Dynamics of RAS Mutations in Liquid Biopsies in Metastatic Colorectal Cancer Patients-Case Series and Literature Review. J Pers Med 2024; 14:750. [PMID: 39064004 PMCID: PMC11278408 DOI: 10.3390/jpm14070750] [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: 04/25/2024] [Revised: 05/29/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Liquid biopsies can accurately identify molecular alterations in patients with colorectal cancer with high concordance with tissue analysis and shorter turnaround times. Circulating tumor (ct) DNA analysis can be used for diagnosing and monitoring tumor evolution in patients with metastatic colorectal cancer who are treated with EGFR inhibitors. In this article, we reported three clinical cases to illustrate the relevance of RAS mutations identified in ctDNA samples of patients with wild-type metastatic colorectal cancer who received an EGFR inhibitor plus chemotherapy as first-line treatment. The identification of RAS mutations in these patients is one of the most frequently identified mechanisms of acquired resistance. However, detecting a KRAS mutation via liquid biopsy can be caused by inter-tumor heterogeneity or it can be a false positive due to clonal hematopoiesis. More research is needed to determine whether ctDNA monitoring may help guide therapy options in metastatic colorectal cancer patients. We performed a literature review to assess the technologies that are used for analysis of RAS mutations on ctDNA, the degree of agreement between tissue and plasma and the importance of tissue/plasma discordant cases.
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Affiliation(s)
- Ionut Popescu
- Faculty of Medicine, Titu Maiorescu University, 031593 Bucharest, Romania; (I.P.); (V.M.C.)
| | - Vlad M. Croitoru
- Faculty of Medicine, Titu Maiorescu University, 031593 Bucharest, Romania; (I.P.); (V.M.C.)
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Irina M. Croitoru-Cazacu
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (S.O.D.)
| | - Ana-Maria Dudau
- Faculty of Medicine, Titu Maiorescu University, 031593 Bucharest, Romania; (I.P.); (V.M.C.)
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Vlad Herlea
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (S.O.D.)
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Olimpia Dima
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania (S.O.D.)
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
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Luo X, Jiang P, Ma J, Li Z, Zhou J, Wei X, A J, Chai J, Lv Y, Cheng P, Cao C, A X. Circulating free DNA as a diagnostic marker for echinococcosis: a systematic review and meta-analysis. Front Microbiol 2024; 15:1413532. [PMID: 39021627 PMCID: PMC11251952 DOI: 10.3389/fmicb.2024.1413532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
Introduction Echinococcosis is a chronic zoonotic disease caused by tapeworms of the genus Echinococcus. The World Health Organization (WHO) has identified encapsulated disease as one of 17 neglected diseases to be controlled or eliminated by 2050. There is no accurate, early, non-invasive molecular diagnostic method to detect echinococcosis. The feasibility of circulating free DNA as a diagnostic method for echinococcosis has yielded inconclusive results in a number of published studies. However, there has been no systematic evaluation to date assessing the overall performance of these assays. We report here the first meta-analysis assessing the diagnostic accuracy of cfDNA in plasma, serum, and urine for echinococcosis. Methods We systematically searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and WeiPu databases up to 17 January 2024, for relevant studies. All analyses were performed using RevMan 5.3, Meta-DiSc 1.4, Stata 17.0, and R 4.3.1 software. The sensitivity, specificity, and other accuracy indicators of circulating free DNA for the diagnosis of echinococcosis were summarized. Subgroup analyses and meta-regression were performed to identify sources of heterogeneity. Results A total of 7 studies included 218 patients with echinococcosis and 214 controls (156 healthy controls, 32 other disease controls (non-hydatid patients), and 26 non-study-targeted echinococcosis controls were included). Summary estimates of the diagnostic accuracy of cfDNA in the diagnosis of echinococcosis were as follows: sensitivity (SEN) of 0.51 (95% CI: 0.45-0.56); specificity (SPE) of 0.99 (95% CI: 0.97-0.99); positive likelihood ratio (PLR) of 11.82 (95% CI: 6.74-20.74); negative likelihood ratio (NLR) of 0.57 (95% CI: 0.41-0.80); diagnostic ratio (DOR) of 36.63 (95% CI: 13.75-97.59); and area under the curve (AUC) value of 0.98 (95% CI: 0.96-1.00). Conclusion Existing evidence indicates that the combined specificity of circulating cfDNA for echinococcosis is high. However, the combined sensitivity performance is unsatisfactory due to significant inter-study heterogeneity. To strengthen the validity and accuracy of our findings, further large-scale prospective studies are required.Systematic review registrationThe systematic review was registered in the International Prospective Register of Systematic Reviews PROSPERO [CRD42023454158]. https://www.crd.york.ac.uk/PROSPERO/.
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Affiliation(s)
- Xiaoqin Luo
- Qinghai University, Xining, China
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
| | | | | | - Zian Li
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
| | - Jianwu Zhou
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
| | | | - Jide A
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
| | - Jinping Chai
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
| | - Yanke Lv
- Qinghai University, Xining, China
| | | | | | - Xiangren A
- Qinghai University, Xining, China
- Department of Clinical Laboratory, Qinghai Provincial People’s Hospital, Xining, China
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Wang H, Zhang Y, Zhang H, Cao H, Mao J, Chen X, Wang L, Zhang N, Luo P, Xue J, Qi X, Dong X, Liu G, Cheng Q. Liquid biopsy for human cancer: cancer screening, monitoring, and treatment. MedComm (Beijing) 2024; 5:e564. [PMID: 38807975 PMCID: PMC11130638 DOI: 10.1002/mco2.564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 04/16/2024] [Accepted: 04/23/2024] [Indexed: 05/30/2024] Open
Abstract
Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy-to-operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real-time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy-based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.
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Affiliation(s)
- Hao Wang
- Department of NeurosurgeryThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Yi Zhang
- Department of NeurosurgeryThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Hao Zhang
- Department of NeurosurgeryThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Hui Cao
- Department of PsychiatryThe School of Clinical Medicine, Hunan University of Chinese MedicineChangshaChina
- Department of PsychiatryBrain Hospital of Hunan Province (The Second People’s Hospital of Hunan Province)ChangshaChina
| | - Jinning Mao
- Health Management CenterThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Xinxin Chen
- Department of NeurosurgeryThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Liangchi Wang
- Department of NeurosurgeryFengdu People's Hospital, ChongqingChongqingChina
| | - Nan Zhang
- College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Peng Luo
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouChina
| | - Ji Xue
- Department of NeurosurgeryTraditional Chinese Medicine Hospital Dianjiang ChongqingChongqingChina
| | - Xiaoya Qi
- Health Management CenterThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Xiancheng Dong
- Department of Cerebrovascular DiseasesDazhou Central HospitalSichuanChina
| | - Guodong Liu
- Department of NeurosurgeryThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingChina
| | - Quan Cheng
- Department of NeurosurgeryXiangya Hospital, Central South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaChina
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Abstract
The cumulative pool of cell-free DNA (cfDNA) molecules within bodily fluids represents a highly dense and multidimensional information repository. This "biological mirror" provides real-time insights into the composition, function, and dynamics of the diverse genomes within the body, enabling significant advancements in personalized molecular medicine. However, effective use of this information necessitates meticulous classification of distinct cfDNA subtypes with exceptional precision. While cfDNA molecules originating from different sources exhibit numerous genetic, epigenetic, and physico-chemical variations, they also share common features that complicate analyses. Considerable progress has been achieved in mapping the landscape of cfDNA features, their clinical correlations, and optimizing extraction procedures, analytical approaches, bioinformatics pipelines, and machine learning algorithms. Nevertheless, preanalytical workflows, despite their profound impact on cfDNA measurements, have not progressed at a corresponding pace. In this perspective article, we emphasize the pivotal role of robust preanalytical procedures in the development and clinical integration of cfDNA assays, highlighting persistent obstacles and emerging challenges.
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Affiliation(s)
- Abel J Bronkhorst
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, Munich, Germany
| | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, Munich, Germany
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Parigger T, Gassner FJ, Drothler S, Scherhäufl C, Hödlmoser A, Schultheis L, Bakar AA, Huemer F, Greil R, Geisberger R, Weiss L, Zaborsky N. Combined DNA Analysis from Stool and Blood Samples Improves Tumor Tracking and Assessment of Clonal Heterogeneity in Localized Rectal Cancer Patients. Technol Cancer Res Treat 2024; 23:15330338241252706. [PMID: 38766867 PMCID: PMC11104029 DOI: 10.1177/15330338241252706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 03/20/2024] [Accepted: 04/08/2024] [Indexed: 05/22/2024] Open
Abstract
Objectives: In this study, stool samples were evaluated for tumor mutation analysis via a targeted next generation sequencing (NGS) approach in a small patient cohort suffering from localized rectal cancer. Introduction: Colorectal cancer (CRC) causes the second highest cancer-related death rate worldwide. Thus, improvements in disease assessment and monitoring that may facilitate treatment allocation and allow organ-sparing "watch-and-wait" treatment strategies are highly relevant for a significant number of CRC patients. Methods: Stool-based results were compared with mutation profiles derived from liquid biopsies and the gold standard procedure of tumor biopsy from the same patients. A workflow was established that enables the detection of de-novo tumor mutations in stool samples of CRC patients via ultra-sensitive cell-free tumor DNA target enrichment. Results: Notably, only a 19% overall concordance was found in mutational profiles across the compared sample specimens of stool, tumor, and liquid biopsies. Conclusion: Based on these results, the analysis of stool and liquid biopsy samples can provide important additional information on tumor heterogeneity and potentially on the assessment of minimal residual disease and clonal tumor evolution.
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Affiliation(s)
- Thomas Parigger
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Franz Josef Gassner
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Stephan Drothler
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
- Department of Biosciences, Paris-Lodron-University Salzburg, Salzburg, Austria
| | - Christian Scherhäufl
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
- Department of Biosciences, Paris-Lodron-University Salzburg, Salzburg, Austria
| | - Alexandra Hödlmoser
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Lena Schultheis
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Aryunni Abu Bakar
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
- Department of Biosciences, Paris-Lodron-University Salzburg, Salzburg, Austria
| | - Florian Huemer
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Richard Greil
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Roland Geisberger
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Lukas Weiss
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Nadja Zaborsky
- Department Laboratory of Immunological and Molecular Cancer Research-Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria
- Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
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Yao S, Han Y, Yang M, Jin K, Lan H. Integration of liquid biopsy and immunotherapy: opening a new era in colorectal cancer treatment. Front Immunol 2023; 14:1292861. [PMID: 38077354 PMCID: PMC10702507 DOI: 10.3389/fimmu.2023.1292861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/03/2023] [Indexed: 12/18/2023] Open
Abstract
Immunotherapy has revolutionized the conventional treatment approaches for colorectal cancer (CRC), offering new therapeutic prospects for patients. Liquid biopsy has shown significant potential in early screening, diagnosis, and postoperative monitoring by analyzing circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). In the era of immunotherapy, liquid biopsy provides additional possibilities for guiding immune-based treatments. Emerging technologies such as mass spectrometry-based detection of neoantigens and flow cytometry-based T cell sorting offer new tools for liquid biopsy, aiming to optimize immune therapy strategies. The integration of liquid biopsy with immunotherapy holds promise for improving treatment outcomes in colorectal cancer patients, enabling breakthroughs in early diagnosis and treatment, and providing patients with more personalized, precise, and effective treatment strategies.
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Affiliation(s)
- Shiya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yuejun Han
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Mengxiang Yang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
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Mattox AK, Douville C, Wang Y, Popoli M, Ptak J, Silliman N, Dobbyn L, Schaefer J, Lu S, Pearlman AH, Cohen JD, Tie J, Gibbs P, Lahouel K, Bettegowda C, Hruban RH, Tomasetti C, Jiang P, Chan KA, Lo YMD, Papadopoulos N, Kinzler KW, Vogelstein B. The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer. Cancer Discov 2023; 13:2166-2179. [PMID: 37565753 PMCID: PMC10592331 DOI: 10.1158/2159-8290.cd-21-1252] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/16/2022] [Accepted: 08/09/2023] [Indexed: 08/12/2023]
Abstract
Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance. SIGNIFICANCE The origin of excess cfDNA in patients with cancer is unknown. Using cfDNA methylation patterns, we determined that neither the tumor nor the surrounding normal tissue contributes this excess cfDNA-rather it comes from leukocytes. This finding suggests that cancers have a systemic impact on cell turnover or DNA clearance. See related commentary by Thierry and Pisareva, p. 2122. This article is featured in Selected Articles from This Issue, p. 2109.
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Affiliation(s)
- Austin K. Mattox
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Christopher Douville
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Yuxuan Wang
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Maria Popoli
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Janine Ptak
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Natalie Silliman
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Lisa Dobbyn
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Joy Schaefer
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Steve Lu
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Alexander H. Pearlman
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Joshua D. Cohen
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Jeanne Tie
- Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria 3021, Australia
- Department of Medical Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Peter Gibbs
- Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria 3021, Australia
- Department of Medical Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Kamel Lahouel
- Division of Mathematics for Cancer Evolution and Early Detection, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010
| | - Chetan Bettegowda
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287
| | - Ralph H. Hruban
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Cristian Tomasetti
- Division of Mathematics for Cancer Evolution and Early Detection, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010
| | - Peiyong Jiang
- State Key Laboratory of Translational Oncology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
- Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China
| | - K.C. Allen Chan
- State Key Laboratory of Translational Oncology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
- Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China
| | - Yuk Ming Dennis Lo
- State Key Laboratory of Translational Oncology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
- Centre for Novostics, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong SAR, China
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Kenneth W. Kinzler
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Bert Vogelstein
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287
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10
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Zhang J, Wu J, Wang G, He L, Zheng Z, Wu M, Zhang Y. Extracellular Vesicles: Techniques and Biomedical Applications Related to Single Vesicle Analysis. ACS NANO 2023; 17:17668-17698. [PMID: 37695614 DOI: 10.1021/acsnano.3c03172] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Extracellular vesicles (EVs) are extensively dispersed lipid bilayer membrane vesicles involved in the delivery and transportation of molecular payloads to certain cell types to facilitate intercellular interactions. Their significant roles in physiological and pathological processes make EVs outstanding biomarkers for disease diagnosis and treatment monitoring as well as ideal candidates for drug delivery. Nevertheless, differences in the biogenesis processes among EV subpopulations have led to a diversity of biophysical characteristics and molecular cargos. Additionally, the prevalent heterogeneity of EVs has been found to substantially hamper the sensitivity and accuracy of disease diagnosis and therapeutic monitoring, thus impeding the advancement of clinical applications. In recent years, the evolution of single EV (SEV) analysis has enabled an in-depth comprehension of the physical properties, molecular composition, and biological roles of EVs at the individual vesicle level. This review examines the sample acquisition tactics prior to SEV analysis, i.e., EV isolation techniques, and outlines the current state-of-the-art label-free and label-based technologies for SEV identification. Furthermore, the challenges and prospects of biomedical applications based on SEV analysis are systematically discussed.
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Affiliation(s)
- Jie Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Jiacheng Wu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Guanzhao Wang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Luxuan He
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Ziwei Zheng
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Minhao Wu
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yuanqing Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
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11
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Santini D, Botticelli A, Galvano A, Iuliani M, Incorvaia L, Gristina V, Taffon C, Foderaro S, Paccagnella E, Simonetti S, Fazio F, Scagnoli S, Pomati G, Pantano F, Perrone G, De Falco E, Russo A, Spinelli GP. Network approach in liquidomics landscape. J Exp Clin Cancer Res 2023; 42:193. [PMID: 37542343 PMCID: PMC10401883 DOI: 10.1186/s13046-023-02743-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/27/2023] [Indexed: 08/06/2023] Open
Abstract
Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.
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Affiliation(s)
- Daniele Santini
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | - Andrea Botticelli
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | - Antonio Galvano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Michele Iuliani
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Lorena Incorvaia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Valerio Gristina
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Chiara Taffon
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico Di Roma, Rome, Italy
| | - Simone Foderaro
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Elisa Paccagnella
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.So Della Repubblica 79, 04100, Latina, Italy
| | - Sonia Simonetti
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Federico Fazio
- UOC Oncologia Territoriale, Polo Pontino, La Sapienza Università Di Roma, Latina, Italy.
| | - Simone Scagnoli
- Oncologia Medica A, Policlinico Umberto 1, La Sapienza Università Di Roma, Rome, Italy
| | | | - Francesco Pantano
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Selcetta, Italy
| | - Giuseppe Perrone
- Anatomical Pathology Operative Research Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Department of Medicine and Surgery, Research Unit of Anatomical Pathology, Università Campus Bio-Medico Di Roma, Rome, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.So Della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, 80122, Naples, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Gian Paolo Spinelli
- UOC Oncologia Territoriale, Polo Pontino, La Sapienza Università Di Roma, Latina, Italy
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Lastraioli E, Bettiol A, Iorio J, Limatola E, Checcacci D, Parisi E, Bianchi C, Arcangeli A, Iannopollo M, Di Costanzo F, Di Lieto M. Evaluation of RAS Mutational Status in Liquid Biopsy to Monitor Disease Progression in Metastatic Colorectal Cancer Patients. Cells 2023; 12:1458. [PMID: 37296579 PMCID: PMC10253213 DOI: 10.3390/cells12111458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/09/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
In this study we evaluated both~ K- and N-RAS mutations in plasma samples from patients with metastatic colorectal cancer by means of the BEAMing technology, and we assessed their diagnostic performance compared to RAS analyses performed on tissue. The sensitivity of BEAMing in identifying KRAS mutations was of 89.5%, with a fair specificity. The agreement with tissue analysis was moderate. The sensitivity for NRAS was high with a good specificity, and the agreement between tissue analysis and BEAMing was fair. Interestingly, significantly higher mutant allele fraction (MAF) levels were detected in patients with G2 tumors, liver metastases, and in those who did not receive surgery. NRAS MAF level was significantly higher in patients with mucinous adenocarcinoma and for those with lung metastases. A sharp increase in the MAF values was observed in patients who moved towards disease progression. More strikingly, molecular progression always anticipated the radiological one in these patients. These observations pave the way to the possibility of using liquid biopsy to monitor patients during treatment, and to enable oncologists to anticipate interventions compared to radiological analyses. This will allow time to be saved and ensure a better management of metastatic patients in the near future.
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Affiliation(s)
- Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Complex Dynamics Study Centre (CSDC), University of Florence, 50100 Florence, Italy
| | - Alessandra Bettiol
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elvira Limatola
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
- Medical Oncology, S.S. Cosma e Damiano Hospital, 51017 Pescia, Italy
| | - Daniele Checcacci
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
- Medical Oncology, S.S. Cosma e Damiano Hospital, 51017 Pescia, Italy
| | - Erica Parisi
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
- Medical Oncology, S.S. Cosma e Damiano Hospital, 51017 Pescia, Italy
| | - Cristina Bianchi
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
- Medical Oncology, S.S. Cosma e Damiano Hospital, 51017 Pescia, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Complex Dynamics Study Centre (CSDC), University of Florence, 50100 Florence, Italy
| | - Mauro Iannopollo
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
- Medical Oncology, S.S. Cosma e Damiano Hospital, 51017 Pescia, Italy
| | - Francesco Di Costanzo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy
| | - Marco Di Lieto
- Medical Oncology, S. Jacopo Hospital, 51100 Pistoia, Italy
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Di Sario G, Rossella V, Famulari ES, Maurizio A, Lazarevic D, Giannese F, Felici C. Enhancing clinical potential of liquid biopsy through a multi-omic approach: A systematic review. Front Genet 2023; 14:1152470. [PMID: 37077538 PMCID: PMC10109350 DOI: 10.3389/fgene.2023.1152470] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/20/2023] [Indexed: 04/05/2023] Open
Abstract
In the last years, liquid biopsy gained increasing clinical relevance for detecting and monitoring several cancer types, being minimally invasive, highly informative and replicable over time. This revolutionary approach can be complementary and may, in the future, replace tissue biopsy, which is still considered the gold standard for cancer diagnosis. "Classical" tissue biopsy is invasive, often cannot provide sufficient bioptic material for advanced screening, and can provide isolated information about disease evolution and heterogeneity. Recent literature highlighted how liquid biopsy is informative of proteomic, genomic, epigenetic, and metabolic alterations. These biomarkers can be detected and investigated using single-omic and, recently, in combination through multi-omic approaches. This review will provide an overview of the most suitable techniques to thoroughly characterize tumor biomarkers and their potential clinical applications, highlighting the importance of an integrated multi-omic, multi-analyte approach. Personalized medical investigations will soon allow patients to receive predictable prognostic evaluations, early disease diagnosis, and subsequent ad hoc treatments.
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14
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Hadipour M, Fasihi Harandi M, Mirhendi H, Yousofi Darani H. Diagnosis of echinococcosis by detecting circulating cell-free DNA and miRNA. Expert Rev Mol Diagn 2023; 23:133-142. [PMID: 36756744 DOI: 10.1080/14737159.2023.2178903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
INTRODUCTION Diagnosis of echinococcosis is difficult and usually performed based on clinical findings, imaging, and serological test. However, all of them have limitations, especially in follow-up approaches. AREAS COVERED Detection of cell-free DNA (cfDNA) and micro-RNA (miRNA) is currently a hot topic for diagnosis of echinococcosis diseases. For detecting cell-free DNA in echinococcosis patient's samples such as sera, some techniques are based on next-generation sequencing (NGS), DNA-deep sequencing, some are based on PCR-based methods, and a few works related to the detection of miRNA for the diagnosis of human echinococcosis. EXPERT OPINION In the detection of cell-free DNA in echinococcosis patient' samples, NGS and DNA-deep sequencing have shown high level of sensitivity, but are not suitable for routine clinical examination as they are expensive and inaccessible in the majority of endemic areas. However, PCR-based methods have shown a sensitivity of about 20-25%. To improve the sensitivity of these tests, improving the DNA extraction method, designing appropriate primers for detecting short-length fragments of circulating DNA, using a higher volume of a serum sample, and application of more sensitive PCR methods are recommended. In the field of miRNA detection, further works are recommended.
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Affiliation(s)
- Mahboubeh Hadipour
- Department of parasitology and mycology, Faculty of medicine, Isfahan University of Medical sciences, Isfahan, Iran
| | - Majid Fasihi Harandi
- Research center for Hydatid disease in Iran, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein Mirhendi
- Department of parasitology and mycology, Faculty of medicine, Isfahan University of Medical sciences, Isfahan, Iran
| | - Hossein Yousofi Darani
- Department of parasitology and mycology, Faculty of medicine, Isfahan University of Medical sciences, Isfahan, Iran
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Miller AM, Karajannis MA. Current Role and Future Potential of CSF ctDNA for the Diagnosis and Clinical Management of Pediatric Central Nervous System Tumors. J Natl Compr Canc Netw 2022; 20:1363-1369. [PMID: 36509077 PMCID: PMC10050207 DOI: 10.6004/jnccn.2022.7093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/28/2022] [Indexed: 12/15/2022]
Abstract
Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.
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Affiliation(s)
- Alexandra M. Miller
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
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Osumi H, Ishizuka N, Takashima A, Kumekawa Y, Nakano D, Shiozawa M, Denda T, Sawada R, Ouchi K, Wakatsuki T, Narikazu B, Kato K, Yamaguchi K, Shinozaki E. Multicentre single-arm phase II trial evaluating the safety and effiCacy of Panitumumab and iRinOtecan in NeoRAS Wild-type mEtaStatic colorectal cancer patientS (C-PROWESS trial): study protocol. BMJ Open 2022; 12:e063071. [PMID: 36581973 PMCID: PMC9438189 DOI: 10.1136/bmjopen-2022-063071] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION A new concept of 'NeoRAS wild-type (WT)', which means conversion of RAS status from RAS mutant to RAS WT after treatment, has been reported. Previous observational and proof-of-concept studies have demonstrated the efficacy of epidermal growth factor receptor inhibitors in patients with NeoRAS WT metastatic colorectal cancer (mCRC). Moreover, posthoc biomarker analyses of these studies have suggested that not only the RAS status in the circulating tumour DNA (ctDNA) but also other gene mutational status may be useful as biomarkers of epidermal growth factor receptor inhibitors for NeoRAS WT mCRC. METHODS AND ANALYSIS This trial is a multicentre, single-arm, phase II trial to assess the efficacy and safety of panitumumab plus irinotecan therapy for patients with NeoRAS mCRC. The key eligibility criteria include RAS mutant mCRC initially proven in tumour tissue refractory or intolerant to fluoropyrimidine, oxaliplatin and irinotecan; RAS WT in ctDNA (defined as plasma mutant allele frequencies of all RAS ≤0.1%) within 28 days before enrolment and Eastern Cooperative Oncology Group performance status ≤2. The primary endpoint is the response rate. The target sample size is 30 patients. Biomarker analyses are planned to be performed using next-generation sequencing-based ctDNA analysis. ETHICS AND DISSEMINATION This study was approved by the certified review board of National Cancer Center Hospital. The main results of the trial will be presented in international meetings and in medical journals. TRIAL REGISTRATION NUMBER s031210565.
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Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, Japan
| | - Naoki Ishizuka
- Department of Clinical Trial Planning and Management, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yosuke Kumekawa
- Divison of Gastrointestinal Oncology, Saitama Cancer Center, Saitama, Japan
| | - Daisuke Nakano
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Manabu Shiozawa
- Department of Surgery, Kanagawa Cancer Center, Kanagawa, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Ryoichi Sawada
- Division of Gastroenterology and Hepatology, Jikei University Hospital, Tokyo, Japan
| | - Kota Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterology, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, Japan
| | - Boku Narikazu
- Department of Medical Oncology and General Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterology, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, Japan
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17
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Malla M, Loree JM, Kasi PM, Parikh AR. Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices. J Clin Oncol 2022; 40:2846-2857. [PMID: 35839443 PMCID: PMC9390824 DOI: 10.1200/jco.21.02615] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/04/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
There exists a tremendous opportunity in identifying and determining the appropriate predictive and prognostic biomarker(s) for risk stratification of patients with colorectal cancers (CRCs). Circulating tumor DNA (ctDNA) has emerged as a promising prognostic and possibly predictive biomarker in the personalized management of patients with CRCs. The disease is particularly suited to a liquid biopsy-based approach since there is a great deal of shedding of circulating tumor fragments (cells, DNA, methylation markers, etc). ctDNA has been shown to have several potential applications, including detecting minimal residual disease (MRD), monitoring for early recurrence, molecular profiling, and therapeutic response prediction. The utility of ctDNA has broadened from its initial use in the advanced/metastatic setting for molecular profiling and detection of acquired resistance mechanisms, toward identifying MRD, as well as early detection. Prospective studies such as CIRCULATE, COBRA, Dynamic II/III, and ACT3 are underway in the MRD setting to further understand how ctDNA may be used to inform clinical decision making using both tumor-informed and tumor-agnostic platforms. These prospective studies use ctDNA to guide management of patients with CRC and will be critical to help guide how and where ctDNA should or should not be used in clinical decision making. It is also important to understand that there are different types of ctDNA liquid biopsy platforms, each with advantages and disadvantages in different clinical indications. This review provides an overview of the current and evolving use of ctDNA in CRC.
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Affiliation(s)
- Midhun Malla
- West Virginia University School of Medicine, Section of Hematology/Oncology, Morgantown, WV
| | - Jonathan M Loree
- BC Cancer/The University of British Columbia, Division of Medical Oncology, Vancouver, BC, Canada
| | - Pashtoon Murtaza Kasi
- Weill Cornell Medicine, Meyer Cancer Center, Englander Institute of Precision Medicine, New York, NY
| | - Aparna Raj Parikh
- Harvard Medical School, Massachusetts General Hospital Cancer Center, Tucker Gosnell Center for Gastrointestinal Malignancies, Termeer Center for Targeted Therapies, Boston, MA
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Hot-Spot-Specific Probe (HSSP) for Rapid and Accurate Detection of KRAS Mutations in Colorectal Cancer. BIOSENSORS 2022; 12:bios12080597. [PMID: 36004993 PMCID: PMC9406089 DOI: 10.3390/bios12080597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022]
Abstract
Detection of oncogene mutations has significance for early diagnosis, customized treatment, treatment progression, and drug resistance monitoring. Here, we introduce a rapid, sensitive, and specific mutation detection assay based on the hot-spot-specific probe (HSSP), with improved clinical utility compared to conventional technologies. We designed HSSP to recognize KRAS mutations in the DNA of colorectal cancer tissues (HSSP-G12D (GGT→GAT) and HSSP-G13D (GGC→GAC)) by integration with real-time PCR. During the PCR analysis, HSSP attaches to the target mutation sequence for interference with the amplification. Then, we determine the mutation detection efficiency by calculating the difference in the cycle threshold (Ct) values between HSSP-G12D and HSSP-G13D. The limit of detection to detect KRAS mutations (G12D and G13D) was 5–10% of the mutant allele in wild-type populations. This is superior to the conventional methods (≥30% mutant allele). In addition, this technology takes a short time (less than 1.5 h), and the cost of one sample is as low as USD 2. We verified clinical utility using 69 tissue samples from colorectal cancer patients. The clinical sensitivity and specificity of the HSSP assay were higher (84% for G12D and 92% for G13D) compared to the direct sequencing assay (80%). Therefore, HSSP, in combination with real-time PCR, provides a rapid, highly sensitive, specific, and low-cost assay for detecting cancer-related mutations. Compared to the gold standard methods such as NGS, this technique shows the possibility of the field application of rapid mutation detection and may be useful in a variety of applications, such as customized treatment and cancer monitoring.
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19
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Paulson V, Konnick EQ, Lockwood CH. When Tissue Is the Issue. Clin Lab Med 2022; 42:485-496. [DOI: 10.1016/j.cll.2022.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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20
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Temraz S, Nasr R, Mukherji D, Kreidieh F, Shamseddine A. Liquid Biopsy Derived Circulating Tumor Cells and Circulating Tumor DNA as Novel Biomarkers in Hepatocellular Carcinoma. Expert Rev Mol Diagn 2022; 22:507-518. [PMID: 35758097 DOI: 10.1080/14737159.2022.2094706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The diagnosis of hepatocellular carcinoma (HCC) is made at a relatively advanced stage resulting in poor prognosis. Alpha-fetoprotein and liver ultrasound have limited accuracy as biomarkers in HCC. Liver biopsy provides information on tumor biology; however, it is invasive and holds high threat of tumor seeding. Thus, more accurate and less invasive approaches are needed. AREAS COVERED Highly sensitive liquid biopsy assays have made possible the detection and analysis of cells or organelles such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived exosomes. Here, we focus on CTCs and ctDNA components of liquid biopsy and their clinical application as diagnostic, prognostic and predictive biomarkers in HCC. Unlike tissue biopsy, liquid biopsy involves attaining a sample at several time frames in an easy and a non-invasive manner. They have been efficacious in detecting and classifying cancer, in predicting treatment response, in monitoring disease relapse and in identifying mechanisms of resistance to targeted therapies. EXPERT OPINION Although interesting and highly promising, liquid biopsy techniques still have many obstacles to overcome before their wide spread clinical application sees the light. It is expected that these techniques will be incorporated into traditional methodologies for better diagnostic, predictive and prognostic results.
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Affiliation(s)
- Sally Temraz
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Deborah Mukherji
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Firas Kreidieh
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
| | - Ali Shamseddine
- Department of internal medicine, Hematology/Oncology division, American University of Beirut Medical Center, Riad El Solh, Beirut, Lebanon
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21
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Malla M, Parikh AR. Evolving Role of Circulating Tumor DNA and Emerging Targeted Therapy in Colorectal Cancer. Hematol Oncol Clin North Am 2022; 36:583-601. [DOI: 10.1016/j.hoc.2022.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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22
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Biomarker-Based Evaluation of Treatment Response and Surveillance of HPV-Associated Squamous Cell Carcinoma. CURRENT OTORHINOLARYNGOLOGY REPORTS 2022. [DOI: 10.1007/s40136-021-00386-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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23
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Zhang Y, Wang Y, Su X, Wang P, Lin W. The Value of Circulating Circular RNA in Cancer Diagnosis, Monitoring, Prognosis, and Guiding Treatment. Front Oncol 2021; 11:736546. [PMID: 34722285 PMCID: PMC8551378 DOI: 10.3389/fonc.2021.736546] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 12/31/2022] Open
Abstract
Liquid biopsy includes non-invasive analysis of circulating tumor-derived substances. It is a novel, innovative cancer screening tool that overcomes the limitations of current invasive tissue examinations in precision oncology. Circular RNA (circRNA) is a recent, novel, and attractive liquid biomarker showing stability, abundance, and high specificity in various diseases, especially in human cancers. This review focused on the emerging potential of human circRNA in body fluids as the liquid biopsy biomarkers for cancers and the methods used to detect the circRNA expression and summarized the construction of circRNA biomarkers in body fluids for treating human cancers and their limitations before they become part of routine clinical medicine. Furthermore, the future opportunities and challenges of translating circRNAs in liquid biopsy into clinical practices were explored.
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Affiliation(s)
- Yunjing Zhang
- Department of Nephrology, The Fourth Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Jinhua, China
| | - Ying Wang
- Department of Nephrology, The Fourth Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Jinhua, China
| | - Xinwan Su
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Wang
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiqiang Lin
- Department of Nephrology, The Fourth Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Jinhua, China
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Fan H, Gai W, Zhang L, Ma Y, Wang H, Chen X, Dong J, Zhang Y, Bao H, Zhou Y, Ren L, Cairang Y, Hou L, Ren B, Wang Z, Wang Z, Song C. Parasite Circulating Cell-free DNA in the Blood of Alveolar Echinococcosis Patients as a Diagnostic and Treatment-Status Indicator. Clin Infect Dis 2021; 73:e246-e251. [PMID: 33146713 DOI: 10.1093/cid/ciaa1679] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Alveolar echinococcosis (AE) is a serious parasitic disease caused by the larvae of Echinococcus multilocularis. It is the less common but substantially more deadly of the 2 major echinococcosis diseases that can occur globally but are concentrated in central Asia. METHODS We analyzed parasite circulating cell-free DNA (cfDNA) in 149 plasma samples using a DNA sequencing-based method (105 AE, 16 cystic echinococcosis, 4 liver cancer, 4 gallstones, and 20 healthy volunteers). After identifying the Echinococcus-specific cfDNA (Em-cfDNA) sequences in the samples, we determined whether Em-cfDNA could be used for AE diagnosis and as a potential indicator of the effectiveness of surgical treatment. We also examined potential associations between Em-cfDNA levels and clinical features of AE patients. RESULTS Our work demonstrates that varying reads of Em-cfDNA were detectable in the plasma of 100% of preoperative AE patients and that all of the non-AE patients and healthy volunteers were negative. Em-cfDNA has good sensitivity and specificity for the diagnosis of AE. We also found that Em-cfDNA levels apparently have reference value for evaluating the therapeutic efficacy of surgery interventions for AE lesions. Finally, our analysis revealed that Em-cfDNA levels can reflect meaningful information about lesion size in preoperative AE patients. CONCLUSIONS We demonstrate that sequencing-based monitoring of Em-cfDNA can be used in the clinic as a powerful diagnostic indicator for AE. We also note that there is a strong potential for use of this liquid-biopsy method to monitor ongoing disease status in postintervention AE patients.
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Affiliation(s)
- Haining Fan
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Wei Gai
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China, National Engineering Research Center for Beijing Biochip Technology, Beijing, China, CapitalBio Corporation, Beijing, China
| | - Lingqiang Zhang
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Yanyan Ma
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Haijiu Wang
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Xiaoping Chen
- Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Dong
- Beijng Tsinghua Changgung Hospital, Belling, China
| | - Yan Zhang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China, National Engineering Research Center for Beijing Biochip Technology, Beijing, China, CapitalBio Corporation, Beijing, China
| | - Haihua Bao
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Ying Zhou
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Li Ren
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Yangdan Cairang
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Lizhao Hou
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Bin Ren
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Zhan Wang
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Zhixin Wang
- Qinghai University Affiliated Hospital, Xining, China, Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, China
| | - Cuidan Song
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China, National Engineering Research Center for Beijing Biochip Technology, Beijing, China, CapitalBio Corporation, Beijing, China
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Evaluation of RAS mutational status through BEAMing assay to monitor disease progression of metastatic colorectal cancer: a case report. Anticancer Drugs 2021; 31:979-982. [PMID: 32889896 DOI: 10.1097/cad.0000000000000923] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Since the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutations: one in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.
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26
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Masfarré L, Vidal J, Fernández-Rodríguez C, Montagut C. ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC). Cancers (Basel) 2021; 13:2869. [PMID: 34201274 PMCID: PMC8226638 DOI: 10.3390/cancers13122869] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/15/2022] Open
Abstract
Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.
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Affiliation(s)
- Laura Masfarré
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
| | - Joana Vidal
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
- Cancer Research Program, FIMIM, Hospital del Mar, 08003 Barcelona, Spain
| | | | - Clara Montagut
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
- Cancer Research Program, FIMIM, Hospital del Mar, 08003 Barcelona, Spain
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Nakajima H, Kotani D, Bando H, Kato T, Oki E, Shinozaki E, Sunakawa Y, Yamazaki K, Yuki S, Nakamura Y, Yamanaka T, Yoshino T, Ohta T, Taniguchi H, Kagawa Y. REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer. BMC Cancer 2021; 21:674. [PMID: 34098908 PMCID: PMC8186219 DOI: 10.1186/s12885-021-08395-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/23/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
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Affiliation(s)
- Hiromichi Nakajima
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Daisuke Kotani
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kentaro Yamazaki
- Divison of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshiaki Nakamura
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | - Hiroya Taniguchi
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshinori Kagawa
- Department of Colorectal Surgery, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan.
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Shanmugam A, Hariharan AK, Hasina R, Nair JR, Katragadda S, Irusappan S, Ravichandran A, Veeramachaneni V, Bettadapura R, Bhati M, Ramaswamy V, Rao VUS, Bagadia RK, Manjunath A, NML M, Solomon MC, Maji S, Bahadur U, Bettegowda C, Papadopoulos N, Lingen MW, Hariharan R, Gupta V, Agrawal N, Izumchenko E. Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma. Cancer 2021; 127:1576-1589. [PMID: 33405231 PMCID: PMC8084899 DOI: 10.1002/cncr.33393] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/16/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck malignancy. Although the survival rate of patients with advanced-stage disease remains approximately 20% to 60%, when detected at an early stage, the survival rate approaches 80%, posing a pressing need for a well validated profiling method to assess patients who have a high risk of developing OCSCC. Tumor DNA detection in saliva may provide a robust biomarker platform that overcomes the limitations of current diagnostic tests. However, there is no routine saliva-based screening method for patients with OCSCC. METHODS The authors designed a custom next-generation sequencing panel with unique molecular identifiers that covers coding regions of 7 frequently mutated genes in OCSCC and applied it on DNA extracted from 121 treatment-naive OCSCC tumors and matched preoperative saliva specimens. RESULTS By using stringent variant-calling criteria, mutations were detected in 106 tumors, consistent with a predicted detection rate ≥88%. Moreover, mutations identified in primary malignancies were also detected in 93% of saliva samples. To ensure that variants are not errors resulting in false-positive calls, a multistep analytical validation of this approach was performed: 1) re-sequencing of 46 saliva samples confirmed 88% of somatic variants; 2) no functionally relevant mutations were detected in saliva samples from 11 healthy individuals without a history of tobacco or alcohol; and 3) using a panel of 7 synthetic loci across 8 sequencing runs, it was confirmed that the platform developed is reproducible and provides sensitivity on par with droplet digital polymerase chain reaction. CONCLUSIONS The current data highlight the feasibility of somatic mutation identification in driver genes in saliva collected at the time of OCSCC diagnosis.
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Affiliation(s)
| | | | - Rifat Hasina
- University of Chicago, Section of Otolaryngology-Head and Neck Surgery, Chicago, USA
| | | | | | | | | | | | | | | | | | - Vishal US Rao
- HealthCare Global (HCG) Cancer Centre, Bangalore, India
| | | | | | - Manjunath NML
- HealthCare Global (HCG) Cancer Centre, Bangalore, India
| | | | | | | | - Chetan Bettegowda
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Mark W. Lingen
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | | | | | - Nishant Agrawal
- University of Chicago, Section of Otolaryngology-Head and Neck Surgery, Chicago, USA
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
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Lengyel CG, Hussain S, Trapani D, El Bairi K, Altuna SC, Seeber A, Odhiambo A, Habeeb BS, Seid F. The Emerging Role of Liquid Biopsy in Gastric Cancer. J Clin Med 2021; 10:2108. [PMID: 34068319 PMCID: PMC8153353 DOI: 10.3390/jcm10102108] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
(1) Background: Liquid biopsy (LB) is a novel diagnostic method with the potential of revolutionizing the prevention, diagnosis, and treatment of several solid tumors. The present paper aims to summarize the current knowledge and explore future possibilities of LB in the management of metastatic gastric cancer. (2) Methods: This narrative review examined the most recent literature on the use of LB-based techniques in metastatic gastric cancer and the current LB-related clinical trial landscape. (3) Results: In gastric cancer, the detection of circulating cancer cells (CTCs) has been recognized to have a prognostic role in all the disease stages. In the setting of localized disease, cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) qualitative and quantitative detection have the potential to inform on the risk of cancer recurrence and metastatic dissemination. In addition, gastric cancer-released exosomes may play an essential part in metastasis formation. In the metastatic setting, the levels of cfDNA show a positive correlation with tumor burden. There is evidence that circulating tumor microemboli (CTM) in the blood of metastatic patients is an independent prognostic factor for shorter overall survival. Gastric cancer-derived exosomal microRNAs or clonal mutations and copy number variations detectable in ctDNA may contribute resistance to chemotherapy or targeted therapies, respectively. There is conflicting and limited data on CTC-based PD-L1 verification and cfDNA-based Epstein-Barr virus detection to predict or monitor immunotherapy responses. (4) Conclusions: Although preliminary studies analyzing LBs in patients with advanced gastric cancer appear promising, more research is required to obtain better insights into the molecular mechanisms underlying resistance to systemic therapies. Moreover, validation and standardization of LB methods are crucial before introducing them in clinical practice. The feasibility of repeatable, minimally invasive sampling opens up the possibility of selecting or dynamically changing therapies based on prognostic risk or predictive biomarkers, such as resistance markers. Research is warranted to exploit a possible transforming area of cancer care.
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Affiliation(s)
| | - Sadaqat Hussain
- North West Cancer Center, Altnagelvin Hospital, Londonderry BT47 6SB, UK;
| | - Dario Trapani
- European Institute of Oncology, IRCCS, 20141 Milan, Italy;
| | | | | | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Andrew Odhiambo
- Unit of Medical Oncology, Department of Clinical Medicine, University of Nairobi, Nairobi 30197, Kenya;
| | - Baker Shalal Habeeb
- Department of Medical Oncology, Shaqlawa Teaching Hospital, Shaqlawa, Erbil 44005, Iraq;
| | - Fahmi Seid
- School of Medicine and Health Sciences, Hawassa University, Hawassa 1560, Ethiopia;
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Practices and expectations on the use of circulating tumor DNA in colorectal cancer patients: A bi-national AGEO/AIOM/GERCOR/FFCD/FRENCH survey. Clin Res Hepatol Gastroenterol 2021; 45:101681. [PMID: 33785445 DOI: 10.1016/j.clinre.2021.101681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 03/22/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Increasing evidence shows that circulating tumor DNA (ctDNA) is a valuable tool in providing molecular, prognostic, predictive and dynamic information in colorectal cancer (CRC) patients. This study aimed to make a picture of knowledge, practice, attitudes and expectations about ctDNA in CRC patients. MATERIAL AND METHODS An online CRC-ctdna survey was distributed from November 2019 to January 2020 to French and Italian cooperative and scientific groups of Hepato-Gastroenterologists (HGE), Medical Oncologists (MO), Radiotherapists (RT) and Digestive Surgeons (DS). RESULTS Overall, 307 physicians completed the survey (57% Italian; 43% French). Most of them were MO (62%) and HGE (24%). Affiliations were University Hospital (48%), Cancer Center (21%), General Hospital (21%) and Private Hospital (10%). Notably, half of respondents declared to have access to ctDNA in their daily practice. Of them, 53% uses ctDNA to assess RAS/BRAF status only, 46% for RAS/BRAF with other mutations and 1% only for other mutations. MO and HGE identified quick RAS profiling (P = 0.031) as the main reason of interest in the use of ctDNA. Physicians from University Hospitals and Cancer Centers prescribed more ctDNA (P < 0.001) and more often in house (P < 0.001). The main future expectations concerning ctDNA were to guide therapeutic strategies in metastatic (78%) and adjuvant (73%) settings, and to better/quicker profile disease at baseline (56%). CONCLUSION Half of participants can order ctDNA in their daily practice. Molecular profiling of metastatic patients remains the main goal of ctDNA use and ctDNA-based therapeutic strategies are an expectation for the future in both adjuvant and metastatic settings.
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Yi JM. DNA Methylation Change Profiling of Colorectal Disease: Screening towards Clinical Use. Life (Basel) 2021; 11:life11050412. [PMID: 33946400 PMCID: PMC8147151 DOI: 10.3390/life11050412] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Colon cancer remains one of the leading causes of cancer-related deaths worldwide. Transformation of colon epithelial cells into invasive adenocarcinomas has been well known to be due to the accumulation of multiple genetic and epigenetic changes. In the past decade, the etiology of inflammatory bowel disease (IBD) which is characterized by chronic inflammation of the intestinal mucosa, was only partially explained by genetic studies providing susceptibility loci, but recently epigenetic studies have provided critical evidences affecting IBD pathogenesis. Over the past decade, A deep understanding of epigenetics along with technological advances have led to identifying numerous genes that are regulated by promoter DNA hypermethylation in colorectal diseases. Recent advances in our understanding of the role of DNA methylation in colorectal diseases could improve a multitude of powerful DNA methylation-based biomarkers, particularly for use as diagnosis, prognosis, and prediction for therapeutic approaches. This review focuses on the emerging potential for translational research of epigenetic alterations into clinical utility as molecular biomarkers. Moreover, this review discusses recent progress regarding the identification of unknown hypermethylated genes in colon cancers and IBD, as well as their possible role in clinical practice, which will have important clinical significance, particularly in the era of the personalized medicine.
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Affiliation(s)
- Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Korea;
- Innovative Therapeutics Research Institute, College of Medicine, Inje University, Busan 47392, Korea
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Li Y, Zheng Y, Wu L, Li J, Ji J, Yu Q, Dai W, Feng J, Wu J, Guo C. Current status of ctDNA in precision oncology for hepatocellular carcinoma. J Exp Clin Cancer Res 2021; 40:140. [PMID: 33902698 PMCID: PMC8074474 DOI: 10.1186/s13046-021-01940-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/06/2021] [Indexed: 01/12/2023] Open
Abstract
The conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China.
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China.
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Johansson G, Kaltak M, Rîmniceanu C, Singh AK, Lycke J, Malmeström C, Hühn M, Vaarala O, Cardell S, Ståhlberg A. Ultrasensitive DNA Immune Repertoire Sequencing Using Unique Molecular Identifiers. Clin Chem 2021; 66:1228-1237. [PMID: 32814950 DOI: 10.1093/clinchem/hvaa159] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Immune repertoire sequencing of the T-cell receptor can identify clonotypes that have expanded as a result of antigen recognition or hematological malignancies. However, current sequencing protocols display limitations with nonuniform amplification and polymerase-induced errors during sequencing. Here, we developed a sequencing method that overcame these issues and applied it to γδ T cells, a cell type that plays a unique role in immunity, autoimmunity, homeostasis of intestine, skin, adipose tissue, and cancer biology. METHODS The ultrasensitive immune repertoire sequencing method used PCR-introduced unique molecular identifiers. We constructed a 32-panel assay that captured the full diversity of the recombined T-cell receptor delta loci in γδ T cells. The protocol was validated on synthetic reference molecules and blood samples of healthy individuals. RESULTS The 32-panel assay displayed wide dynamic range, high reproducibility, and analytical sensitivity with single-nucleotide resolution. The method corrected for sequencing-depended quantification bias and polymerase-induced errors and could be applied to both enriched and nonenriched cells. Healthy donors displayed oligoclonal expansion of γδ T cells and similar frequencies of clonotypes were detected in both enrichment and nonenriched samples. CONCLUSIONS Ultrasensitive immune repertoire sequencing strategy enables quantification of individual and specific clonotypes in a background that can be applied to clinical as well as basic application areas. Our approach is simple, flexible, and can easily be implemented in any molecular laboratory.
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Affiliation(s)
- Gustav Johansson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Translational Science & Experimental Medicine, Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), Gothenburg, Sweden
| | - Melita Kaltak
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Cristiana Rîmniceanu
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 7A, University of Gothenburg, Gothenburg, Sweden
| | - Avadhesh K Singh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 7A, University of Gothenburg, Gothenburg, Sweden
| | - Jan Lycke
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Clas Malmeström
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Michael Hühn
- Translational Science & Experimental Medicine, Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), Gothenburg, Sweden
| | - Outi Vaarala
- Respiratory Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Susanna Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 7A, University of Gothenburg, Gothenburg, Sweden
| | - Anders Ståhlberg
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
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Wang YH, Song Z, Hu XY, Wang HS. Circulating tumor DNA analysis for tumor diagnosis. Talanta 2021; 228:122220. [PMID: 33773726 DOI: 10.1016/j.talanta.2021.122220] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 01/10/2023]
Abstract
Tumor is a kind of abnormal organism generated by the proliferation and differentiation of cells in the body under the action of various initiating and promoting factors, which seriously threatens human life and health. Tumorigenesis is a gradual process that involves multistage reactions and the accumulation of mutations. Gene mutation usually occurs during tumorigenesis, and can be used for tumor diagnosis. Early diagnosis is the most effective way to improve the cure rate and reduce the mortality rate. Among the peripheral blood circulating tumor DNA (ctDNA), gene mutation in keeping with tumor cells can be detected, which can potentially replace tumor tissue section for early diagnosis. It has been considered as a liquid biopsy marker with good clinical application prospect. However, the high fragmentation and low concentration of ctDNA in blood result in the difficulty of tumor stage determination. Therefore, high sensitive and specific mutation detection methods have been developed to detect trace mutant ctDNA. At present, the approaches include digital PCR (dPCR), Bead, Emulsion, Amplification and Magnetic (BEAMing), Next Generation Sequencing (NGS), Amplification Refractory Mutation System (ARMS), etc. In this paper, the principle, characteristics, latest progress and application prospects of these methods are reviewed, which will facilitate researchers to choose appropriate ctDNA detection approaches.
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Affiliation(s)
- Yi-Hui Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China
| | - Zhen Song
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China
| | - Xin-Yuan Hu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China
| | - Huai-Song Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
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Dasari A, Morris VK, Allegra CJ, Atreya C, Benson AB, Boland P, Chung K, Copur MS, Corcoran RB, Deming DA, Dwyer A, Diehn M, Eng C, George TJ, Gollub MJ, Goodwin RA, Hamilton SR, Hechtman JF, Hochster H, Hong TS, Innocenti F, Iqbal A, Jacobs SA, Kennecke HF, Lee JJ, Lieu CH, Lenz HJ, Lindwasser OW, Montagut C, Odisio B, Ou FS, Porter L, Raghav K, Schrag D, Scott AJ, Shi Q, Strickler JH, Venook A, Yaeger R, Yothers G, You YN, Zell JA, Kopetz S. ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nat Rev Clin Oncol 2020; 17:757-770. [PMID: 32632268 PMCID: PMC7790747 DOI: 10.1038/s41571-020-0392-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2020] [Indexed: 02/07/2023]
Abstract
An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.
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Affiliation(s)
- Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Chloe Atreya
- University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Patrick Boland
- Department of Medicine, Roswell Park Cancer Center, Buffalo, NY, USA
| | - Ki Chung
- Division of Hematology & Oncology, Medical University of South Carolina, Charleston, SC, USA
| | - Mehmet S Copur
- CHI Health St Francis Cancer Treatment Center, Grand Island, NE, USA
| | - Ryan B Corcoran
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Dustin A Deming
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Andrea Dwyer
- University of Colorado Cancer Center, Aurora, CO, USA
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas J George
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, FL, USA
| | - Marc J Gollub
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Stanley R Hamilton
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaclyn F Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Howard Hochster
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MD, USA
| | - Federico Innocenti
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA
| | - Atif Iqbal
- Section of Colorectal Surgery, Division of Surgery, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Samuel A Jacobs
- National Adjuvant Surgical and Bowel Project Foundation/NRG Oncology, Pittsburgh, PA, USA
| | - Hagen F Kennecke
- Department of Oncology, Virginia Mason Cancer Institute, Seattle, WA, USA
| | - James J Lee
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Christopher H Lieu
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA
| | - Heinz-Josef Lenz
- Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - O Wolf Lindwasser
- Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Clara Montagut
- Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Pompeu Fabra, Barcelona, Spain
| | - Bruno Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fang-Shu Ou
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Laura Porter
- Patient Advocate, NCI Colon Task Force, Boston, MA, USA
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Deborah Schrag
- Division of Population Sciences, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Aaron J Scott
- Division of Hematology and Oncology, Banner University of Arizona Cancer Center, Tucson, AZ, USA
| | - Qian Shi
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Alan Venook
- University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Y Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason A Zell
- Department of Epidemiology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Dudley JC, Diehn M. Detection and Diagnostic Utilization of Cellular and Cell-Free Tumor DNA. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:199-222. [PMID: 33228464 DOI: 10.1146/annurev-pathmechdis-012419-032604] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Because cancer is caused by an accumulation of genetic mutations, mutant DNA released by tumors can be used as a highly specific biomarker for cancer. Although this principle was described decades ago, the advent and falling costs of next-generation sequencing have made the use of tumor DNA as a biomarker increasingly practical. This review surveys the use of cellular and cell-free DNA for the detection of cancer, with a focus on recent technological developments and applications to solid tumors. It covers (a) key principles and technology enabling the highly sensitive detection of tumor DNA; (b) assessment of tumor DNA in plasma, including for genotyping, minimal residual disease detection, and early detection of localized cancer; (c) detection of tumor DNA in body cavity fluids, such as urine or cerebrospinal fluid; and (d) challenges posed to the use of tumor DNA as a biomarker by the phenomenon of benign clonal expansions.
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Affiliation(s)
- Jonathan C Dudley
- Ludwig Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
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Lastraioli E, Antonuzzo L, Fantechi B, Di Cerbo L, Di Costanzo A, Lavacchi D, Armenio M, Arcangeli A, Castiglione F, Messerini L, Di Costanzo F. KRAS and NRAS mutation detection in circulating DNA from patients with metastatic colorectal cancer using BEAMing assay: Concordance with standard biopsy and clinical evaluation. Oncol Lett 2020; 21:15. [PMID: 33240421 PMCID: PMC7681220 DOI: 10.3892/ol.2020.12276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
Patients with metastatic colorectal cancer (mCRC) are routinely screened for either K- and N-RAS to select the appropriate treatment. The present study aimed to evaluate the concordance between K- and NRAS status in the tissue (either primary tumor or metastasis) and the plasma of patients with mCRC and to identify the associations between K- and NRAS mutations in ctDNA and the clinicopathological parameters. Samples from a total of 31 patients with mCRC with measurable disease according to the Response Evaluation Criteria in Solid Tumors were analyzed. For all patients, K- and NRAS status was determined in the tissue by matrix-assisted laser desorption/ionization time of flight mass spectrometry. For the detection of RAS mutations in cell-free tumor DNA also defined as circulating tumor DNA (ctDNA), the OncoBEAM® RAS CRC kit (Sysmex Inostics) was used. A total of 6/31 tissue samples expressed wild-type KRAS, whereas 25/31 presented mutations. In addition, 7/31 plasma samples expressed wild-type KRAS, mutations were detected in 22/31 patients, and for 2/31 patients, the test did not provide a conclusive result. A total of 24/31 patients expressed wild-type NRAS, 6/31 had mutations and 1/21 was not informative. For the KRAS mutational status, a moderate concordance (agreement, 85.18%; Cohen's k, 0.513) between the tissue and plasma analysis was observed; for NRAS, a fair agreement (agreement, 83.33%; Cohen's k, 0.242) was obtained. In conclusion, both tissue and plasma analyses should be performed for the management of patients with mCRC. To better exploit the beads, emulsions, amplification, magnetics (BEAMing) technique in the clinical setting, studies aimed at determining the RAS status to monitor therapy and during follow-up are warranted.
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Affiliation(s)
- Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Beatrice Fantechi
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Luisa Di Cerbo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Alessandro Di Costanzo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Daniele Lavacchi
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Miriam Armenio
- Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy
| | - Francesca Castiglione
- Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy
| | - Francesco Di Costanzo
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, I-50134 Florence, Italy
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Hata T, Mizuma M, Motoi F, Omori Y, Ishida M, Nakagawa K, Hayashi H, Morikawa T, Kamei T, Furukawa T, Unno M. GNAS mutation detection in circulating cell-free DNA is a specific predictor for intraductal papillary mucinous neoplasms of the pancreas, especially for intestinal subtype. Sci Rep 2020; 10:17761. [PMID: 33082481 PMCID: PMC7576136 DOI: 10.1038/s41598-020-74868-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 09/17/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cystic neoplasms (PCNs) are a heterogeneous group with varying risks of malignancy. To explore the clinical utility of liquid biopsy in cyst type classification, we analyzed the GNAS/KRAS mutations in circulating cell-free DNA (cfDNA) obtained from 57 patients with histologically diagnosed PCNs, including 34 with intraductal papillary mucinous neoplasms (IPMNs) and compared the mutant allele prevalence and variant patterns with the paired resected specimens using next-generation sequencing. The positive prevalence of GNAS mutations in cfDNA of patients with IPMN (n = 11, 32%) was significantly higher than that in those with other PCNs (0%, P = 0.002). Conversely, KRAS mutations were detected in cfDNA of only 2 (6%) IPMN patients. The paired-sample comparison revealed highly concordance between the GNAS mutation status of cfDNA and resected IPMN specimens. Similar distributions of GNAS mutation positivity in cfDNA were observed across the different histological grades, whereas IPMNs with intestinal subtype showed a significantly higher prevalence of GNAS mutations than other subtypes (P = 0.030). GNAS mutation positivity in cfDNA was significantly associated with the acellular mucin pool of histological findings in primary IPMN lesions (P = 0.017). Detection of GNAS mutation in cfDNA can serve as a novel biomarker for cyst type classification and differentiation of intestinal subtype IPMN from the other PCNs.
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Affiliation(s)
- Tatsuo Hata
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Yuko Omori
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masaharu Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Kei Nakagawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Hiroki Hayashi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Takanori Morikawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Toru Furukawa
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
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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: 70] [Impact Index Per Article: 14.0] [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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Tuchalska-Czuroń J, Lenart J, Augustyniak J, Durlik M. Clinical value of tissue DNA integrity index in pancreatic cancer. Surgeon 2020; 18:269-279. [PMID: 32156475 DOI: 10.1016/j.surge.2019.10.008] [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: 06/25/2019] [Revised: 10/08/2019] [Accepted: 10/28/2019] [Indexed: 10/24/2022]
Abstract
BACKGROUND DNA integrity index as a blood biomarker is associated with the prognosis of cancer patients. AIMS The primary goal of the study was to examine tissue DNA integrity index (DII) in a group of pancreatic cancer (PC) tumor tissues and control adjacent pancreatic tissues. We also aimed to test the relationship between the tumor tissue DII and the clinicopathological parameters and the overall survival. METHODS In the prospective study, DII was calculated using: the Alu 247/115 ratio, the LINE1 300/79 ratio and the average of the above values, based on the data obtained by real-time PCR. The tumors samples (n = 42) originated from the patients with pathologically confirmed pancreatic ductal adenocarcinoma and the control adjacent pancreatic tissue specimens (n = 32) were received from surgical margins. RESULTS Specimens from the tumors pathologically marked as R1 (microscopic residual tumor) had a significantly higher LINE1 300/79 ratio values than specimens from adjacent normal pancreatic tissue (P<0.05). ROC curve analysis revealed that LINE1 300/79 ratio is a good parameter to distinguish between R0 and R1 tumors (AUC = 0.703, P<0.05). CONCLUSIONS This is the first study exploring the tissue DNA integrity index (DII) in pancreatic cancer. LINE1 DII can be used as auxiliary parameter for objective evaluation of margin status.
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Affiliation(s)
- Julia Tuchalska-Czuroń
- Department of Surgical Research and Transplantology, Medical Research Centre Polish Academy of Sciences, Warsaw, Poland; Diagnostic Radiology Department, Central Clinical Hospital of the MSWiA in Warsaw, Poland.
| | - Jacek Lenart
- Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Justyna Augustyniak
- Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Marek Durlik
- Department of Surgical Research and Transplantology, Medical Research Centre Polish Academy of Sciences, Warsaw, Poland; Department of Gastroenterological Surgery and Transplantation Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland; Clinical Department of Gastroenterological Surgery and Transplantation Medicine, Central Clinical Hospital of the MSWiA in Warsaw, Poland
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Chandrapalan S, Arasaradnam RP. Urine as a biological modality for colorectal cancer detection. Expert Rev Mol Diagn 2020; 20:489-496. [PMID: 32130868 DOI: 10.1080/14737159.2020.1738928] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: The increasing incidence of colorectal cancer (CRC) in young adults warrants early and preferably noninvasive diagnostic modalities. Although the current stool-based assays have had good performance indicators for CRC detection, the overall poor uptake remains a challenging issue. However, alternative blood and urine markers are emerging.Areas covered: This paper discusses the various urinary biomarkers available for the detection of CRC. The more commonly encountered drawbacks are the small number of studies and the size of the study population. We discuss the role of microRNA and ProstaglandinE2 in CRC detection. The emergence of new, low-cost technologies, specifically in the detection of volatile organic compounds (VOCs), presents a promising future. We postulate possible mechanisms for the origin of these VOCs in urine and their role in carcinogenesis.Expert opinion: Urinary biomarkers provide an alternative option to the stool-based screening tests. MicroRNA and ProstaglandinE2 have shown utility in CRC detection. Evidence so far suggests that VOCs could also be a potential biomarker for the detection of CRC. In addition to its interaction within the colon lumen, this altered 'VOC signature' might also play a role in carcinogenesis. Low-cost technology may enable such diagnostic methods to be utilized at the point of care.
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Affiliation(s)
- Subashini Chandrapalan
- Department of Gastroenterology, University Hospital of Coventry and Warwickshire, Coventry, UK
| | - Ramesh P Arasaradnam
- Department of Gastroenterology, University Hospital of Coventry and Warwickshire, Coventry, UK.,Warwick Medical School, University of Warwick, Coventry, UK.,Health, Biological & Experimental Sciences, University of Coventry, Coventry, UK.,School of Health Sciences, University of Leicester, Leicester, UK
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Quirico L, Orso F. The power of microRNAs as diagnostic and prognostic biomarkers in liquid biopsies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3:117-139. [PMID: 35582611 PMCID: PMC9090592 DOI: 10.20517/cdr.2019.103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/24/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
In the last decades, progresses in medical oncology have ameliorated the treatment of patients and their outcome. However, further improvements are still necessary, in particular for certain types of tumors such as pancreatic, gastric, and lung cancer as well as acute myeloid leukemia where early detection and monitoring of the disease are crucial for final patient outcome. Liquid biopsy represents a great advance in the field because it is less invasive, less time-consuming, and safer compared to classical biopsies and it can be useful to monitor the evolution of the disease as well as the response of patients to therapy. Liquid biopsy allows the detection of circulating tumor cells, nucleic acids, and exosomes not only in blood but also in different biological fluids: urine, saliva, pleural effusions, cerebrospinal fluid, and stool. Among the potential biomarkers detectable in liquid biopsies, microRNAs (miRNAs) are gaining more and more attention, since they are easily detectable, quite stable in biological fluids, and show high sensitivity. Many data demonstrate that miRNAs alone or in combination with other biomarkers could improve the diagnostic and prognostic power for many different tumors. Despite this, standardization of methods, sample preparation, and analysis remain challenging and a huge effort should be made to address these issues before miRNA biomarkers can enter the clinic. This review summarizes the main findings in the field of circulating miRNAs in both solid and hematological tumors.
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Affiliation(s)
- Lorena Quirico
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
- Molecular Biotechnology Center (MBC), University of Torino, Torino 10126, Italy
| | - Francesca Orso
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy
- Molecular Biotechnology Center (MBC), University of Torino, Torino 10126, Italy
- Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino 10126, Italy
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Abstract
ctDNA provided by liquid biopsy offers a promising alternative to tumor biopsy as it gives a non-invasive and «real-time» access to the cancer genome and reflects tumor intra and extra heterogeneity. ctDNA has shown growing clinical interest for cancer diagnosis, prognosis, theragnostics, therapeutic monitoring, and clonal evolution tracking. A major technical limit for ctDNA analysis from body fluids is the extremely low proportion of ctDNA compared to non-malignant cell-free DNA, underscoring the need for highly sensitive and specific detection techniques. The control of pre-analytical procedures appears essential for optimal ctDNA analysis and need to be standardized for clinical research applications. This chapter provides insights into major current technologies for ctDNA detection. Overall, PCR-based techniques are able to detect limited molecular alterations and have a high sensitivity suitable for monitoring purposes while NGS-based approaches are broad range molecular screening assays more specifically indicated for treatment selection. We briefly reviewed new technical innovations that are now available for ctDNA detection.
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Affiliation(s)
- Pauline Gilson
- Université de Lorraine, CNRS UMR 7039 CRAN, Institut de Cancérologie de Lorraine, Service de Biopathologie, 54000, Nancy, France.
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Bronkhorst AJ, Ungerer V, Holdenrieder S. Early detection of cancer using circulating tumor DNA: biological, physiological and analytical considerations. Crit Rev Clin Lab Sci 2019:1-17. [PMID: 31865831 DOI: 10.1080/10408363.2019.1700902] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Early diagnosis of cancer improves the efficacy of curative therapies. However, due to the difficulties involved in distinguishing between small early-stage tumors and normal biological variation, early detection of cancer is an extremely challenging task and there are currently no clinically validated biomarkers for a pan-cancer screening test. It is thus of particular significance that increasing evidence indicates the potential of circulating tumor DNA (ctDNA) molecules, which are fragmented segments of DNA shed from tumor cells into adjacent body fluids and the circulatory system, to serve as molecular markers for early cancer detection and thereby allow early intervention and improvement of therapeutic and survival outcomes. This is possible because ctDNA molecules bear cancer-specific fragmentation patterns, nucleosome depletion motifs, and genetic and epigenetic alterations, as distinct from plasma DNA originating from non-cancerous tissues/cells. Compared to traditional biomarkers, ctDNA analysis therefore presents the distinctive advantage of detecting tumor-specific alterations. However, based on a thorough survey of the literature, theoretical and empirical evidence suggests that current ctDNA analysis strategies, which are mainly based on DNA mutation detection, do not demonstrate the necessary diagnostic sensitivity and specificity that is required for broad clinical implementation in a screening context. Therefore, in this review we explain the biological, physiological, and analytical challenges toward the development of clinically meaningful ctDNA tests. In addition, we explore some approaches that can be implemented in order to increase the sensitivity and specificity of ctDNA assays.
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Affiliation(s)
- Abel Jacobus Bronkhorst
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Vida Ungerer
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Stefan Holdenrieder
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
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Yang C, Xia BR, Jin WL, Lou G. Circulating tumor cells in precision oncology: clinical applications in liquid biopsy and 3D organoid model. Cancer Cell Int 2019; 19:341. [PMID: 31866766 PMCID: PMC6918690 DOI: 10.1186/s12935-019-1067-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
Circulating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings-CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development.
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Affiliation(s)
- Chang Yang
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Bai-Rong Xia
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
| | - Wei-Lin Jin
- 2Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China.,3National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai, 200240 People's Republic of China
| | - Ge Lou
- 1Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical University, Harbin, 150086 People's Republic of China
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Abstract
Abstract
Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. This can be achieved by leveraging omics information for accurate molecular characterization of tumors. Tumor tissue biopsies are currently the main source of information for molecular profiling. However, biopsies are invasive and limited in resolving spatiotemporal heterogeneity in tumor tissues. Alternative non-invasive liquid biopsies can exploit patient’s body fluids to access multiple layers of tumor-specific biological information (genomes, epigenomes, transcriptomes, proteomes, metabolomes, circulating tumor cells, and exosomes). Analysis and integration of these large and diverse datasets using statistical and machine learning approaches can yield important insights into tumor biology and lead to discovery of new diagnostic, predictive, and prognostic biomarkers. Translation of these new diagnostic tools into standard clinical practice could transform oncology, as demonstrated by a number of liquid biopsy assays already entering clinical use. In this review, we highlight successes and challenges facing the rapidly evolving field of cancer biomarker research.
Lay Summary
Precision oncology aims to tailor clinical decisions specifically to patients with the objective of improving treatment outcomes. The discovery of biomarkers for precision oncology has been accelerated by high-throughput experimental and computational methods, which can inform fine-grained characterization of tumors for clinical decision-making. Moreover, advances in the liquid biopsy field allow non-invasive sampling of patient’s body fluids with the aim of analyzing circulating biomarkers, obviating the need for invasive tumor tissue biopsies. In this review, we highlight successes and challenges facing the rapidly evolving field of liquid biopsy cancer biomarker research.
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Abstract
The technique of cell-free DNA (cfDNA) analysis, also called liquid biopsy, has been developed over the past several years to serve as a minimal residual disease tool, as has already been done with reliability and robustness in acute leukemias. This technique has important theoretical advantages, including the simplicity of acquiring blood samples, which can easily be repeated over time, its noninvasive and quantitative nature, which provides results consistent with the results obtained from tumor genomic DNA, and its speed and low cost. cfDNA analysis, as the leading tool to quantify somatic mutations, is a major technological leap in the noninvasive management of lymphomas. This technology may empower monitoring and treatment adjustment in real time and enable the quick detection of refractory lymphomas and resistance to routine therapies. Here, we summarize the results that have established the clinical relevance of cfDNA in diagnostic and prognostic stratification and the monitoring of lymphoma treatments.
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Affiliation(s)
- Vincent Camus
- Department of Hematology, Centre Henri Becquerel, 1 Rue D'Amiens, 76038 Rouen Cedex, France
| | - Fabrice Jardin
- Department of Hematology, Centre Henri Becquerel, 1 Rue D'Amiens, 76038 Rouen Cedex, France
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Barnell EK, Kang Y, Wurtzler EM, Griffith M, Chaudhuri AA, Griffith OL. Noninvasive Detection of High-Risk Adenomas Using Stool-Derived Eukaryotic RNA Sequences as Biomarkers. Gastroenterology 2019; 157:884-887.e3. [PMID: 31154021 PMCID: PMC6707888 DOI: 10.1053/j.gastro.2019.05.058] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/18/2019] [Accepted: 05/28/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Erica K Barnell
- McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri; Division of Gastroenterology and Hepatology, Geneoscopy LLC, St Louis, Missouri
| | - Yiming Kang
- Division of Gastroenterology and Hepatology, Geneoscopy LLC, St Louis, Missouri; Department of Computer Science and Engineering, Washington University, St Louis, Missouri
| | | | - Malachi Griffith
- McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri; Department of Genetics, Washington University School of Medicine, St Louis, Missouri; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri
| | - Aadel A Chaudhuri
- Department of Computer Science and Engineering, Washington University, St Louis, Missouri; Department of Genetics, Washington University School of Medicine, St Louis, Missouri; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri.
| | - Obi L Griffith
- McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri; Department of Genetics, Washington University School of Medicine, St Louis, Missouri; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
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Circulating cell-free long DNA fragments predict post-hepatectomy recurrence of colorectal liver metastases. Eur J Surg Oncol 2019; 46:108-114. [PMID: 31431321 DOI: 10.1016/j.ejso.2019.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 08/11/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Most patients with colorectal liver metastases, who undergo hepatectomy, experience recurrence. Although the prognosis is poorer for patients with early recurrence (within 6 months after hepatectomy) compared with later recurrence, no biomarker has been identified to predict early recurrence. Minimal residual disease (MRD) in patients who undergo curative surgery is the main cause of recurrence. In cancer patients, long fragment cell-free DNA is detected, and the presence of long fragments of cell-free DNA after surgery can indicate MRD. In this study, we developed a novel biomarker to predict early recurrence of colorectal liver metastases using cell-free DNA. MATERIALS AND METHODS Forty-one patients with colorectal liver metastases were enrolled. Peripheral blood samples were collected before and at 1 month after hepatectomy. Cell-free DNA was extracted from 1 ml plasma, and the long fragment/β-globin ratio, which can indicate MRD, was measured by real-time polymerase chain reaction. RESULTS Three of 21 patients (14.3%) with decreases in the long cell-free DNA fragment/β-globin ratio after hepatectomy developed early recurrence compared with twelve of 20 patients (60.0%) with an increased ratio (P = 0.002). Patients with a decreased long fragment/β-globin ratio after hepatectomy had significantly longer recurrence-free survival compared with patients with an increased ratio (366 vs 102 days, P < 0.001). CONCLUSION The cell-free DNA long fragment/β-globin ratio may serve as an effective biomarker of early recurrence in patients with colorectal liver metastases, who undergo hepatectomy.
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Vivancos A, Aranda E, Benavides M, Élez E, Gómez-España MA, Toledano M, Alvarez M, Parrado MRC, García-Barberán V, Diaz-Rubio E. Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples. Sci Rep 2019; 9:8976. [PMID: 31222012 PMCID: PMC6586620 DOI: 10.1038/s41598-019-45616-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 06/07/2019] [Indexed: 01/02/2023] Open
Abstract
KRAS mutations are common in colorectal cancer (CRC). In this setting, mutation status determination in circulating-free DNA from blood samples (liquid biopsy) has been shown to be a viable alternative to tissue testing. The objective of this study was to compare the sensitivity of two liquid biopsy methods for detecting KRAS mutations in plasma samples from metastatic CRC patients. Samples with a positive (KRAS-MUT+) result and a mutant allelic fraction (MAF) < 5% according to the OncoBEAM RAS CRC assay were pairly analyzed by the Idylla ctKRAS Mutation Test (n = 116). In a cohort of 71 patients with at least 1 year of follow-up, the progression-free survival (PFS) was determined according to MAF values. Idylla detected KRAS mutations in 81/116 OncoBEAM KRAS-MUT+ samples with MAF < 5% and in 48/79 samples with MAF < 1%. Concordance between OncoBEAM and Idylla significantly improved at higher MAF values. PFS rates at 6 and 12 months tended to be lower in patients with MAF levels between 1% and 5% than in those with levels <1%. OncoBEAM demonstrated greater sensitivity for plasma detection of KRAS mutations than Idylla. Importantly, our data identified a “gray zone” below 1% MAF where Idylla showed reduced KRAS mutation detection, highlighting the importance of an accurate method to provide the mutational status of CRC patients.
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Affiliation(s)
- Ana Vivancos
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
| | - Enrique Aranda
- Department of Medical Oncology, Reina Sofía University Hospital, CIBERONC, Córdoba, Spain
| | - Manuel Benavides
- Department of Medical Oncology, Hospital Universitario Regional y Virgen de la Victoria, Málaga, Spain
| | - Elena Élez
- Department of Medical Oncology Vall d'Hebron Institute of Oncology (CIBERONC), Barcelona, Spain
| | | | - Marta Toledano
- IMIBIC Instituto Maimonides Investigación Biomédica de Córdoba, Córdoba, Spain
| | - Martina Alvarez
- Laboratorio de Biología Molecular del Cáncer. Centro de Investigaciones Médico Sanitarias, Universidad de Málaga, Málaga, Spain
| | - Maria Rosario Chica Parrado
- Laboratorio de Biología Molecular del Cáncer. Centro de Investigaciones Médico Sanitarias, Universidad de Málaga, Málaga, Spain
| | - Vanesa García-Barberán
- Laboratorio de Investigación Traslacional, IdISSC, Hospital Clínico San Carlos, CIBERONC, Madrid, Spain
| | - Eduardo Diaz-Rubio
- Laboratorio de Investigación Traslacional, IdISSC, Hospital Clínico San Carlos, CIBERONC, Madrid, Spain
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