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Gao C, Patel J, Robbins M, Gedvilaite E, Bowman AS, Arora K, Vanderbilt C, Brannon AR, Friedman DN, Kennedy J, Fiala E, Ceyhan-Birsoy O, Dunkel IJ, Weigelt B, Francis JH, Reis-Filho JS, Abramson DH, Mandelker D. Detection and Characterization of RB1 Mosaicism in Patients With Retinoblastoma Receiving cfDNA Test. JAMA Ophthalmol 2025:2833593. [PMID: 40338593 PMCID: PMC12062978 DOI: 10.1001/jamaophthalmol.2025.1079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 03/02/2025] [Indexed: 05/09/2025]
Abstract
Importance Plasma cell-free DNA (cfDNA) testing is increasingly used for disease diagnosis and monitoring in retinoblastoma, with RB1 allele fraction in cfDNA actively corresponding to disease status and treatment response. However, while RB1 mosaicism has been reported in retinoblastoma, its clinical implications and potential impact on cfDNA testing remain unclear. Objectives To identify RB1 mosaicism using paired plasma and buffy coat (containing lymphocytes, monocytes, granulocytes, and platelets) DNA testing, and to characterize the implications of RB1 mosaicism on cfDNA testing outcomes. Design, Setting, and Participants In this cross-sectional study, participants with retinoblastoma underwent testing with MSK-ACCESS (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a clinical assay that combines plasma cfDNA and buffy coat genomic DNA sequencing, enabling the detection and differentiation of somatic, heterozygous, and mosaic variants, between July 2020 and April 2024 at the Memorial Sloan Kettering Cancer Center. Mosaic findings from MSK-ACCESS were correlated with those from a subgroup of patients who concurrently underwent testing using the MSK-IMPACT germline assay. Data analysis was performed from April to September 2024. Exposure RB1 mosaicism in retinoblastoma. Main Outcomes and Measures The RB1 variant allele fractions in cfDNA and buffy coat genomic DNA were used to detect RB1 mosaicism. Results A total of 136 consecutive patients with retinoblastoma (median age at diagnosis, 1.0 year [IQR, 0.4-1.7 years]; 74 [54.4%] female; 67 with bilateral disease and 69 with unilateral disease) who underwent testing with the MSK-ACCESS assay were included. RB1 mosaicism was identified in buffy coat DNA from 20 patients (14.7%), with consistent results detected in all 11 participants tested concurrently by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) germline assay. Four participants with RB1 mosaicism previously tested negative for germline RB1 variants by external laboratories. Compared with heterozygous participants, participants with RB1 mosaicism had a lower risk of developing bilateral disease (91.7% vs 55.0%, respectively; difference, 36.7% [95% CI, 13.8%-59.6%]; P = .002). In cfDNA, the mosaicism variant was detected both before and after treatment, with variant allele fraction initially decreasing after treatment but then stabilizing at levels consistent with mosaicism, despite the absence of clinical disease. Conclusions and Relevance The accurate detection and quantification of RB1 mosaicism are crucial. RB1 mosaicism should be considered when RB1 variants persist in cfDNA after treatment without evidence of disease; failure to do so may lead to false-positive results and overtreatment in patients with RB1 mosaicism. Identifying RB1 mosaicism may improve patient counseling, inform treatment decisions, and enhance surveillance efforts.
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Affiliation(s)
- Chuan Gao
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Juber Patel
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Melissa Robbins
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Erika Gedvilaite
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anita S. Bowman
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kanika Arora
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chad Vanderbilt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - A. Rose Brannon
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Danielle N. Friedman
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer Kennedy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elise Fiala
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ozge Ceyhan-Birsoy
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ira J. Dunkel
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jasmine H. Francis
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Ophthalmology, Weill Cornell Medical Center, New York, New York
| | - Jorge S. Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Cancer Biomarker Development, Oncology Research and Development, AstraZeneca, Gaithersburg, Maryland
| | - David H. Abramson
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Ophthalmology, Weill Cornell Medical Center, New York, New York
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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Aydın Ş, Özdemir S, Adıgüzel A. The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases. J Mol Neurosci 2025; 75:34. [PMID: 40080233 PMCID: PMC11906534 DOI: 10.1007/s12031-025-02317-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/06/2025] [Indexed: 03/15/2025]
Abstract
Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.
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Affiliation(s)
- Şeyma Aydın
- Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Selçuk Özdemir
- Department of Genetics, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey.
| | - Ahmet Adıgüzel
- Department of Molecular Biology and Genetics, Faculty of Science, Atatürk University, Erzurum, Turkey.
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Miyamoto S, Tokuyama T, Okubo Y, Okamura S, Miyauchi S, Furutani M, Kobayashi Y, Odake Y, Oguri N, Uotani Y, Nakashima M, Akiyama R, Sakai T, Ishida M, Nakano Y. Decreased plasma cell-free mitochondrial DNA may be a new biomarker of tachycardia-induced cardiomyopathy in patients with atrial fibrillation. Int J Cardiol 2024; 417:132579. [PMID: 39306290 DOI: 10.1016/j.ijcard.2024.132579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/19/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
OBJECTIVES To determine cell-free mitochondrial DNA (mt-cfDNA) levels in tachycardia-induced cardiomyopathy (TIC) and non-TIC among atrial fibrillation (AF) cases. BACKGROUNDS TIC is a reversible cardiomyopathy resulting from tachyarrhythmias, such as AF. The exact cause of TIC is not fully understood, but mitochondrial dysfunction has been reported in a variety of cardiomyopathies and may be involved in TIC as well. AF is recognized to be associated with systemic inflammation, and studies have shown that in patients with AF have elevated levels of mt-cfDNA increased, and this increase is linked to systemic inflammation. METHODS We enrolled 67 patients with TIC (TIC group) and 671 patients without TIC (non-TIC group), who underwent catheter ablation for AF at our hospital between November 2009 and September 2016 and did not meet the exclusion criteria. We performed quantitative PCR analysis of plasma mt-cfDNA and nuclear-cfDNA and compared clinical factors and these measurements between the two groups. RESULTS Levels of mt-cfDNA were significantly lower in the TIC group than in the non-TIC group (1110.01 vs. 1918.71 copies/μg plasma, P = 0.027), while levels of nuclear-cfDNA were comparable between these two groups. In particular, mt-cfDNA (P = 0.0003, odds ratio [OR] 2.54), non-paroxysmal AF (P < 0.0001, OR 3.07), and diabetes mellitus (P = 0.006, OR 2.36) were identified as independent factors associated with TIC. CONCLUSION There are lower mt-cfDNA in TIC, and decreased plasma levels of circulating mt-cfDNA may be a new biomarker and involve in related mechanisms for AF associated TIC. CONDENSED ABSTRACT Tachycardia-induced cardiomyopathy (TIC) is a reversible cardiomyopathy caused by tachyarrhythmias, such as atrial fibrillation (AF) tachycardia. The pathogenesis of TIC remains incompletely understood, and there is currently no method to predict its development in patients. In this study, we show that cell-free mitochondrial DNA (mt-cfDNA) levels were significantly lower in the TIC group than in the non-TIC group. Persistent AF, coexisting diabetes mellitus, and decreased mt-cfDNA levels were independently associated with TIC. Decreased mt-cfDNA levels may serve as a novel biomarker for predicting TIC in patients with AF.
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Affiliation(s)
- Shogo Miyamoto
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takehito Tokuyama
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yousaku Okubo
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Sho Okamura
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shunsuke Miyauchi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Motoki Furutani
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yusuke Kobayashi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yodo Odake
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoto Oguri
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukimi Uotani
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mika Nakashima
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Rie Akiyama
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takumi Sakai
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mari Ishida
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukiko Nakano
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
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Mishra S, Kumari S, Husain N. Liquid biopsy in gallbladder carcinoma: Current evidence and future prospective. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100280. [PMID: 40027313 PMCID: PMC11863890 DOI: 10.1016/j.jlb.2024.100280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 03/05/2025]
Abstract
Although there have been significant advances in the early detection and treatment of gallbladder cancer (GBC), it is still considered a leading cause of morbidity and mortality. Molecular profiling of tumors is generally performed using samples obtained during surgery or biopsy. However, tissue genotyping has its limitations as it only provides a single snapshot and is susceptible to spatial selection bias due to the tumor heterogeneity. Over the past decade, there has been a remarkable transition from invasive diagnostic methods to non-invasive alternatives, including liquid biopsy, for cancer diagnosis and monitoring. Liquid biopsies have ushered in a new era in clinical oncology, enabling convenient tumor sampling, continuous monitoring through repeated analysis, development of personalized treatment regimens, and assessment of therapy resistance. While peripheral blood is the primary medium for these biopsies, other biological fluids, including urine, saliva, and bile, also serve as valuable sources of information. Currently, the focus of blood-based biopsy analyses is on four main sources of biomarkers for cancer detection and stratification: circulating tumor DNA (ctDNA) or circulating free DNA (cfDNA), circulating tumor cells (CTCs), and extracellular vesicle (EVs). There are over 300 clinical trials either ongoing or actively recruiting participants to investigate the diagnostic and prognostic applications of ctDNA/cfDNA in the context of cancer. This review outlines the current standard of care for individuals with GBC, anticipates future treatment developments, and evaluates the potential applications of liquid biopsies in various clinical contexts. The review addresses ctDNA/cfDNA, CTC, and circulating microRNA and highlights their prospective roles in management of GBC.
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Affiliation(s)
- Sridhar Mishra
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Plastic and Reconstructive Surgery, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Swati Kumari
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Pathology, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Nuzhat Husain
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
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Li JY, Zuo LP, Xu J, Sun CY. Clinical applications of circulating tumor DNA in hematological malignancies: From past to the future. Blood Rev 2024; 68:101237. [PMID: 39261219 DOI: 10.1016/j.blre.2024.101237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024]
Abstract
Liquid biopsy, particularly circulating tumor DNA (ctDNA), has drawn a lot of attention as a non- or minimal-invasive detection approach for clinical applications in patients with cancer. Many hematological malignancies are well suited for serial and repeated ctDNA surveillance due to relatively high ctDNA concentrations and high loads of tumor-specific genetic and epigenetic abnormalities. Progress of detecting technology in recent years has improved sensitivity and specificity significantly, thus broadening and strengthening the potential utilities of ctDNA including early diagnosis, prognosis estimation, treatment response evaluation, minimal residual disease monitoring, targeted therapy selection, and immunotherapy surveillance. This manuscript reviews the detection methodologies, clinical application and future challenges of ctDNA in hematological malignancies, especially for lymphomas, myeloma and leukemias.
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Affiliation(s)
- Jun-Ying Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of science and Technology, Wuhan, Hubei, China
| | - Li-Ping Zuo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of science and Technology, Wuhan, Hubei, China
| | - Jian Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of science and Technology, Wuhan, Hubei, China
| | - Chun-Yan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of science and Technology, Wuhan, Hubei, China.
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Gallardo‐Gómez M, Costas‐Ríos L, Garcia‐Prieto CA, Álvarez‐Rodríguez L, Bujanda L, Barrero M, Castells A, Balaguer F, Jover R, Esteller M, Tardío Baiges A, González‐Carreró Fojón J, Cubiella J, De Chiara L. Serum DNA methylome of the colorectal cancer serrated pathway enables non-invasive detection. Mol Oncol 2024; 18:2696-2713. [PMID: 38129291 PMCID: PMC11547225 DOI: 10.1002/1878-0261.13573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 12/23/2023] Open
Abstract
The clinical relevance of the colorectal cancer serrated pathway is evident, but the screening of serrated lesions remains challenging. We aimed to characterize the serum methylome of the serrated pathway and to evaluate circulating cell-free DNA (cfDNA) methylomes as a potential source of biomarkers for the non-invasive detection of serrated lesions. We collected serum samples from individuals with serrated adenocarcinoma (SAC), traditional serrated adenomas, sessile serrated lesions, hyperplastic polyps and individuals with no colorectal findings. First, we quantified cfDNA methylation with the MethylationEPIC array. Then, we compared the methylation profiles with tissue and serum datasets. Finally, we evaluated the utility of serum cfDNA methylation biomarkers. We identified a differential methylation profile able to distinguish high-risk serrated lesions from no serrated neoplasia, showing concordance with tissue methylation from SAC and sessile serrated lesions. Serum methylation profiles are pathway-specific, clearly separating serrated lesions from conventional adenomas. The combination of ninjurin 2 (NINJ2) and glutamate-rich 1 (ERICH1) methylation discriminated high-risk serrated lesions and SAC with 91.4% sensitivity (64.4% specificity), while zinc finger protein 718 (ZNF718) methylation reported 100% sensitivity for the detection of SAC (96% specificity). This is the first study exploring the serum methylome of serrated lesions. Differential methylation of cfDNA can be used for the non-invasive detection of colorectal serrated lesions.
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Affiliation(s)
- María Gallardo‐Gómez
- CINBIO, Universidade de VigoSpain
- Department of Biochemistry, Genetics and ImmunologyUniversidade de VigoSpain
- Galicia Sur Health Research Institute (IIS Galicia Sur)SERGAS‐UVIGOSpain
| | - Lara Costas‐Ríos
- CINBIO, Universidade de VigoSpain
- Department of Biochemistry, Genetics and ImmunologyUniversidade de VigoSpain
| | - Carlos A. Garcia‐Prieto
- Josep Carreras Leukaemia Research Institute (IJC)BadalonaSpain
- Life Sciences DepartmentBarcelona Supercomputing Center (BSC)Spain
| | - Lara Álvarez‐Rodríguez
- CINBIO, Universidade de VigoSpain
- Department of Biochemistry, Genetics and ImmunologyUniversidade de VigoSpain
| | - Luis Bujanda
- Department of Gastroenterology, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)Universidad del País Vasco (UPV/EHU)San SebastiánSpain
| | - Maialen Barrero
- Department of OncologyHospital Universitario DonostiaSan SebastiánSpain
| | - Antoni Castells
- Gastroenterology Department, Hospital Clínic, IDIBAPS, CIBERehdUniversity of BarcelonaSpain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clínic, IDIBAPS, CIBERehdUniversity of BarcelonaSpain
| | - Rodrigo Jover
- Servicio de Medicina Digestiva, Hospital General Universitario Dr. Balmis ISABIALUniversidad Miguel HernándezAlicanteSpain
| | - Manel Esteller
- Josep Carreras Leukaemia Research Institute (IJC)BadalonaSpain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC)MadridSpain
- Institució Catalana de Recerca i Estudis Avançats (ICREA)BarcelonaSpain
- Physiological Sciences Department, School of Medicine and Health SciencesUniversity of Barcelona (UB)Spain
| | - Antoni Tardío Baiges
- Department of PathologyHospital Álvaro Cunqueiro, Instituto de Investigación Biomédica Galicia SurVigoSpain
| | | | - Joaquín Cubiella
- Department of GastroenterologyComplexo Hospitalario Universitario de Ourense, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)OurenseSpain
| | - Loretta De Chiara
- CINBIO, Universidade de VigoSpain
- Department of Biochemistry, Genetics and ImmunologyUniversidade de VigoSpain
- Galicia Sur Health Research Institute (IIS Galicia Sur)SERGAS‐UVIGOSpain
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Rakshit I, Mandal S, Pal S, Bhattacharjee P. Advancements in bladder cancer detection: a comprehensive review on liquid biopsy and cell-free DNA analysis. THE NUCLEUS 2024. [DOI: 10.1007/s13237-024-00494-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/04/2024] [Indexed: 01/06/2025] Open
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Koukou Z, Panteris E, Manolakos E, Papadopoulos A, Papoulidis I, Relakis K, Sifakis S. Cell‑free fetal DNA at 11‑13 weeks of gestation is not altered in complicated pregnancies. Biomed Rep 2024; 20:69. [PMID: 38495346 PMCID: PMC10941718 DOI: 10.3892/br.2024.1757] [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: 06/19/2023] [Accepted: 12/13/2023] [Indexed: 03/19/2024] Open
Abstract
Non-invasive maternal cell-free fetal DNA (cffDNA) is a promising biomarker for screening common genetic syndromes. Alterations in the expression levels of cffDNA in the maternal circulation have been demonstrated in abnormal pregnancies. However, the results are conflicting. The present study aimed to investigate whether cffDNA levels are associated with pregnancy complications. The study group comprised pregnant women who presented with pregnancy complications, such as preterm birth, gestational hypertension, intrauterine growth retardation, gestational diabetes, polyhydramnios, oligohydramnios, vaginal bleeding and placental abruption. The control group comprised women who had a normal pregnancy course. Blood samples were obtained from 500 pregnant women between 11-13 weeks of gestation. cffDNA was amplified, sequenced and analyzed using the next-generation aneuploidy test of a Panorama-Natera kit. Nuchal translucency (NT) thickness as well as pregnancy associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG) levels were also assessed. Statistical analysis was performed in 494 out of the 500 samples collected with SPSS v.26 using non-parametric methods. The parameters were normalized by the multiples of median (MoM) method. The expression levels of PAPP-A, β-hCG, and the NT mean MoM values were significantly different between the study and control groups (P=0.005, P<0.001 and P=0.007, respectively). However, the expression levels of cffDNA and the mean MoM values were not significantly different between these two groups (P=0.687). The findings of the present study support the conclusion that cffDNA expression is not altered in a series of pregnancy complications. The prognostic value of cffDNA in predicting adverse pregnancy outcomes requires further investigation.
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Affiliation(s)
- Zoi Koukou
- School of Health Sciences, International Hellenic University (IHU), 57400 Thessaloniki, Greece
- Department of Obstetrics and Gynecology, University Hospital of Heraklion, 71500 Heraklion, Greece
| | - Eleftherios Panteris
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Emmanouel Manolakos
- Access to Genome P.C., Clinical Laboratory Genetics, 11528 Thessaloniki, Greece
| | | | - Ioannis Papoulidis
- Access to Genome P.C., Clinical Laboratory Genetics, 11528 Thessaloniki, Greece
| | - Konstantinos Relakis
- Department of Obstetrics and Gynecology, University Hospital of Heraklion, 71500 Heraklion, Greece
| | - Stavros Sifakis
- Department of Obstetrics and Gynecology, University Hospital of Heraklion, 71500 Heraklion, Greece
- Mitera Maternity Hospital, 71202 Heraklion, Greece
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Sawai A, Shida T, Hoshikawa Y, Hatanaka S, Ueda M, Kato Y, Tokinoya K, Natsui H, Kawakami Y, Takekoshi K. Effect of acute moderate-intensity cycling on cfDNA levels considering menstrual cycle phases. Front Sports Act Living 2024; 6:1322295. [PMID: 38348376 PMCID: PMC10859457 DOI: 10.3389/fspor.2024.1322295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/15/2024] [Indexed: 02/15/2024] Open
Abstract
Introduction We aimed to determine the effects of exercise on cell-free DNA (cfDNA) levels and concentration changes during the menstrual cycle in participants with regular menstrual cycles and no exercise habits. Methods Eleven sedentary female students with regular menstrual cycles and ovulation performed bicycle exercises at 60% VO2max for 30 min during the menstrual, ovulatory, and luteal phases. Blood samples were collected before (Pre), immediately after (Post 0), 30 min after (Post 30), and 60 min after (Post 60) exercise. Blood concentrations of ovarian hormones, cfDNA, prostaglandin F2a (PGF2α), interleukin-6 (IL-6), and aromatase were evaluated. Results Based on the concentration of ovarian hormones, seven individuals were finally analyzed. No significant phase difference was observed in cfDNA across all time points. cfDNA (menstrual phase: p = 0.028, ovulatory phase: p = 0.018, and luteal phase: p = 0.048) and aromatase concentrations (menstrual phase: p = 0.040, ovulatory phase: p = 0.039, and luteal phase: p = 0.045) significantly increased from Pre to Post 0 in all phases. Serum estradiol (E2) levels were significantly higher in the luteal phase at all time points than in the menstrual phase (Pre: p < 0.001, Post 0: p < 0.001, Post 30: p = 0.005, and Post 60: p = 0.011); however, serum progesterone (P4) levels were significantly higher in the luteal phase at all time points than in the menstrual (Pre: p < 0.001, Post 0: p < 0.001, Post 30: p < 0.001, and Post 60: p < 0.001) and ovulatory phases (Pre: p = 0.005, Post 0: p = 0.005, Post 30: p = 0.003, and Post 60: p = 0.003). E2 levels significantly increased from Pre to Post 0 in the ovulatory and luteal phases, whereas P4 levels increased in the luteal phase. Progesterone to estradiol level ratio (P4/E2) changes from Pre to Post 0 (%baseline) during the luteal phase were significantly negatively correlated (r = -0.82, p = 0.046) with the changes in cfDNA from Pre to Post 0. Furthermore, the repeated measures correlation between P4/E2 and cfDNA level showed a significant negative correlation in ovulatory and luteal phases. Discussion The results indicate that while resting cfDNA levels are unlikely to be affected by a woman's menstrual cycle, the increase in cfDNA after exercise is higher in the ovulatory phase (when only E2 increases) and lower in the luteal phase (when E2 and P4 increase with exercise) compared to that in the menstrual phase (when E2 and P4 are in low levels), suggesting the contribution of increased ovarian hormone levels after exercise.
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Affiliation(s)
- Akemi Sawai
- Research Institute of Physical Fitness, Japan Women’s College of Physical Education, Setagaya City, Japan
- Department of Clinical Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan
| | - Takashi Shida
- Department of Clinical Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan
- Research Team for Promoting Independence and Mental Health, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi City, Japan
| | - Yoshihiro Hoshikawa
- Department of Sports Science, Japan Women’s College of Physical Education, Setagaya City, Japan
| | - Sho Hatanaka
- Research Team for Promoting Independence and Mental Health, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi City, Japan
| | - Mashiro Ueda
- Master’s Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba City, Japan
| | - Yuri Kato
- Master’s Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba City, Japan
| | - Katsuyuki Tokinoya
- Department of Clinical Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan
- Embodied Wisdom Division, Center for Liberal Education and Learning, Sophia University, Chiyoda City, Japan
| | - Hiroaki Natsui
- Department of Sports and Health Science, Japan Women’s College of Physical Education, Setagaya City, Japan
| | - Yasushi Kawakami
- Department of Clinical Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan
| | - Kazuhiro Takekoshi
- Department of Clinical Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan
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10
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Kowal-Wisniewska E, Jaskiewicz K, Bartochowska A, Kiwerska K, Ustaszewski A, Gorecki T, Giefing M, Paluszczak J, Wierzbicka M, Jarmuz-Szymczak M. Towards effectiveness of cell free DNA based liquid biopsy in head and neck squamous cell carcinoma. Sci Rep 2024; 14:2251. [PMID: 38278927 PMCID: PMC10817923 DOI: 10.1038/s41598-024-52031-5] [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] [Accepted: 01/12/2024] [Indexed: 01/28/2024] Open
Abstract
Liquid biopsy is a minimally invasive procedure, that uses body fluids sampling to detect and characterize cancer fingerprints. It is of great potential in oncology, however there are challenges associated with the proper handling of liquid biopsy samples that need to be addressed to implement such analysis in patients' care. Therefore, in this study we performed optimization of pre-analytical conditions and detailed characterization of cfDNA fraction (concentration, length, integrity score) in surgically treated HNSCC patients (n = 152) and healthy volunteers (n = 56). We observed significantly higher cfDNA concentration in patients compared to healthy controls (p < 0.0001) and a time dependent decrease of cfDNA concentration after tumor resection. Our results also revealed a significant increase of cfDNA concentration with age in both, healthy volunteers (p = 0.04) and HNSCC patients (p = 0.000002). Moreover, considering the multitude of HNSCC locations, we showed the lack of difference in cfDNA concentration depending on the anatomical location. Furthermore, we demonstrated a trend toward higher cfDNA length (range 35-10380 and 500-10380 bp) in the group of patients with recurrence during follow-up. In conclusion, our study provide a broad characterization of cfDNA fractions in HNSCC patients and healthy controls. These findings point to several aspects necessary to consider when implementing liquid biopsy in clinical practice including: (I) time required for epithelial regeneration to avoid falsely elevated levels of cfDNA not resulting from active cancer, (II) age-related accumulation of nucleic acids accompanied by less efficient elimination of cfDNA and (III) higher cfDNA length in patients with recurrence during follow-up, reflecting predominance of tumor necrosis.
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Affiliation(s)
- Ewelina Kowal-Wisniewska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland.
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
| | - Katarzyna Jaskiewicz
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
| | - Anna Bartochowska
- Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Kiwerska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
- Department of Tumor Pathology, Greater Poland Cancer Centre, Poznan, Poland
| | - Adam Ustaszewski
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
| | - Tomasz Gorecki
- Faculty of Mathematics and Computer Science, Adam Mickiewicz University, Poznan, Poland
| | - Maciej Giefing
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
| | - Jaroslaw Paluszczak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland
| | - Malgorzata Wierzbicka
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
- Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Poznan, Poland
- Faculty of Medicine Wroclaw, University of Science and Technology, Wroclaw, Poland
| | - Malgorzata Jarmuz-Szymczak
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland
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11
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Erlitzki N, Kohli RM. An Overview of Global, Local, and Base-Resolution Methods for the Detection of 5-Hydroxymethylcytosine in Genomic DNA. Methods Mol Biol 2024; 2842:325-352. [PMID: 39012604 DOI: 10.1007/978-1-0716-4051-7_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/17/2024]
Abstract
The discovery of 5-hydroxymethylcytosine (5hmC) as a common DNA modification in mammalian genomes has ushered in new areas of inquiry regarding the dynamic epigenome. The balance between 5hmC and its precursor, 5-methylcytosine (5mC), has emerged as a determinant of key processes including cell fate specification, and alterations involving these bases have been implicated in the pathogenesis of various diseases. The identification of 5hmC separately from 5mC initially posed a challenge given that legacy epigenetic sequencing technologies could not discriminate between these two most abundant modifications, a significant blind spot considering their potentially functionally opposing roles. The growing interest in 5hmC, as well as in the Ten-Eleven Translocation (TET) family enzymes that catalyze its generation and further oxidation to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC), has spurred the development of versatile methods for 5hmC detection. These methods enable the quantification and localization of 5hmC in diverse biological samples and, in some cases, at the resolution of individual nucleotides. However, navigating this growing toolbox of methods for 5hmC detection can be challenging. Here, we detail existing and emerging methods for the detection, quantification, and localization of 5hmC at global, locus-specific, and base resolution levels. These methods are discussed in the context of their advantages and limitations, with the goal of providing a framework to help guide researchers in choosing the level of resolution and the associated method that could be most suitable for specific needs.
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Affiliation(s)
- Noa Erlitzki
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rahul M Kohli
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
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12
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Adhit KK, Wanjari A, Menon S, K S. Liquid Biopsy: An Evolving Paradigm for Non-invasive Disease Diagnosis and Monitoring in Medicine. Cureus 2023; 15:e50176. [PMID: 38192931 PMCID: PMC10772356 DOI: 10.7759/cureus.50176] [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: 08/23/2023] [Accepted: 12/08/2023] [Indexed: 01/10/2024] Open
Abstract
Liquid biopsy stands as an innovative instrument in the realm of precision medicine, enabling non-invasive disease diagnosis and the early detection of cancer. Liquid biopsy helps in the extraction of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and cell-free DNA (cfDNA) from blood samples and other body fluids, thereby facilitating disease diagnosis and prediction of high-risk patients. Various techniques such as advanced sequencing methods and biomarker-based cell capture have led to the isolation and study of the different biomarkers such as ctDNA, cfDNA, and CTCs. These biopsies also have immense potential in the early detection and diagnosis of various diseases across all medical specialties, prediction and screening of high-risk cases, and detection of different immune response patterns in response to infectious diseases, and also help in predicting treatment outcomes. Although liquid biopsy has the potential to disrupt the field of medical diagnosis, it is met by various challenges such as limited tumor-derived components, less specificity, and inadequate advancement in methods to isolate biomarkers. Despite all these challenges, liquid biopsies provide the potential to become a minimally invasive method of diagnosis that would facilitate real-time monitoring of patients, which differentiates them from traditional tissue biopsies. This article aims to provide a complete overview of the current technologies, different biomarkers, and body fluids that can be used in liquid biopsy and its clinical applications and the potential impact that liquid biopsy holds in the field of precision medicine, facilitating early diagnosis and prompt management of various diseases and cancers.
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Affiliation(s)
- Kanishk K Adhit
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Anil Wanjari
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sharanya Menon
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Siddhaarth K
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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13
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Islam MS, Gopalan V, Lam AK, Shiddiky MJA. Current advances in detecting genetic and epigenetic biomarkers of colorectal cancer. Biosens Bioelectron 2023; 239:115611. [PMID: 37619478 DOI: 10.1016/j.bios.2023.115611] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023]
Abstract
Colorectal carcinoma (CRC) is the third most common cancer in terms of diagnosis and the second in terms of mortality. Recent studies have shown that various proteins, extracellular vesicles (i.e., exosomes), specific genetic variants, gene transcripts, cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and altered epigenetic patterns, can be used to detect, and assess the prognosis of CRC. Over the last decade, a plethora of conventional methodologies (e.g., polymerase chain reaction [PCR], direct sequencing, enzyme-linked immunosorbent assay [ELISA], microarray, in situ hybridization) as well as advanced analytical methodologies (e.g., microfluidics, electrochemical biosensors, surface-enhanced Raman spectroscopy [SERS]) have been developed for analyzing genetic and epigenetic biomarkers using both optical and non-optical tools. Despite these methodologies, no gold standard detection method has yet been implemented that can analyze CRC with high specificity and sensitivity in an inexpensive, simple, and time-efficient manner. Moreover, until now, no study has critically reviewed the advantages and limitations of these methodologies. Here, an overview of the most used genetic and epigenetic biomarkers for CRC and their detection methods are discussed. Furthermore, a summary of the major biological, technical, and clinical challenges and advantages/limitations of existing techniques is also presented.
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Affiliation(s)
- Md Sajedul Islam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine & Dentistry, Griffith University, Gold Coast Campus, Southport, QLD, 4222, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia; Pathology Queensland, Gold Coast University Hospital, Southport, QLD, 4215, Australia
| | - Muhammad J A Shiddiky
- Rural Health Research Institute, Charles Sturt University, Orange, NSW, 2800, Australia.
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14
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Diaz PM, Leehans A, Ravishankar P, Daily A. Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges. Biomark Insights 2023; 18:11772719231204508. [PMID: 37846373 PMCID: PMC10576933 DOI: 10.1177/11772719231204508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/12/2023] [Indexed: 10/18/2023] Open
Abstract
Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.
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Affiliation(s)
- Paola Monterroso Diaz
- Namida Lab Inc., Fayetteville, AR, USA
- University of Arkansas, Department of Biomedical Engineering, Fayetteville, AR, USA
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15
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Leick KM, Tomanek-Chalkley A, Coleman KL, Chan CHF. Peritoneal Cell-Free Tumor DNA is a Biomarker of Locoregional and Peritoneal Recurrence in Resected Pancreatic Ductal Adenocarcinomas. Ann Surg Oncol 2023; 30:6652-6660. [PMID: 37303025 DOI: 10.1245/s10434-023-13701-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/10/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND Recurrence after curative-intent pancreatectomy for pancreatic ductal adenocarcinomas (PDAC) is quite frequent with locoregional and peritoneal recurrence in about one-third of cases. We hypothesize that peritoneal cell-free tumor DNA (ptDNA) present in the intraoperative peritoneal lavage (PL) fluid may be used as a predictive biomarker of locoregional and peritoneal recurrence. PATIENTS AND METHODS Under institutional review board (IRB)-approved protocol, pre- and postresection PL fluids were collected from PDAC patients undergoing curative-intent pancreatectomy. PL fluids from PDAC patients with pathologically proven peritoneal metastasis were also collected as positive controls. Cell-free DNA was extracted from PL fluids. Droplet digital PCR (ddPCR) was performed using ddPCR KRAS G12/G13 screening kit. Recurrence-free survival (RFS) based on KRAS-mutant ptDNA level was determined using Kaplan-Meier methods. RESULTS KRAS-mutant ptDNA was detected in PL fluids from all PDAC patients. KRAS-mutant ptDNA was detected in 11/21 (52%) preresection and 15/18 (83%) postresection PL fluid samples. With a median follow-up of 23.6 months, 12 patients developed recurrence (8 locoregional/peritoneal recurrence, 9 pulmonary/hepatic recurrence); 5/8 (63%) and 6/6 (100%) patients with mutant allele frequency (MAF) of > 0.10% in pre- and postresection PL fluids, respectively, developed recurrence. Using a cutoff value of 0.10% MAF, the presence of KRAS-mutant ptDNA in postresection PL fluid predicted a significantly shortened time to locoregional and peritoneal recurrence (median RFS of 8.9 months versus not reached, P = 0.003). CONCLUSIONS This study suggests that ptDNA in postresection PL fluids may be a useful biomarker to predict locoregional and peritoneal recurrence in resected PDAC patients.
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Affiliation(s)
- Katie M Leick
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Ann Tomanek-Chalkley
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Kristen L Coleman
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Carlos H F Chan
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
- Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
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16
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Liu B, Sun Z, Zhou R, Shen D, Zhu S, Chen L, Huang G. Novel insights into biomarkers of progression in Desmoid tumor. Front Oncol 2023; 13:1206800. [PMID: 37601698 PMCID: PMC10434506 DOI: 10.3389/fonc.2023.1206800] [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: 04/16/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Desmoid tumor (DT) is a rare neoplasm characterized by the proliferation of myofibroblastic cells that infiltrates and invades adjacent tissues. Due to its locally aggressive and recurrent nature, DT often causes local symptoms and can be challenging to manage clinically. Therefore, identifying biomarkers that can predict the progression of DT and guide treatment decisions is critical. This review summarizes several biomarkers that have been implicated in active surveillance (AS) and the prediction of postoperative recurrence and attempts to elucidate their underlying mechanisms. Some of these novel markers could provide prognostic value for clinicians, and ultimately help facilitate optimal and accurate therapeutic decisions for DT.
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Affiliation(s)
- Baiqi Liu
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zefang Sun
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Rui Zhou
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Dingcheng Shen
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shuai Zhu
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lu Chen
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Gengwen Huang
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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17
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Luo WD, Wang YP, Lv J, Liu Y, Qu YQ, Xu XF, Yang LJ, Lin ZC, Wang LN, Chen RH, Yang JJ, Zeng YL, Zhang RL, Huang BX, Yun XY, Wang XY, Song LL, Wu JH, Wang XX, Chen X, Zhang W, Wang HM, Qu LQ, Liu MH, Liu L, Law BYK, Wong VKW. Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis. Nat Commun 2023; 14:4394. [PMID: 37474626 PMCID: PMC10359253 DOI: 10.1038/s41467-023-40113-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 07/11/2023] [Indexed: 07/22/2023] Open
Abstract
The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.
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Affiliation(s)
- Wei-Dan Luo
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yu-Ping Wang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
| | - Jun Lv
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
| | - Yong Liu
- The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
| | - Yuan-Qing Qu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xiong-Fei Xu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Li-Jun Yang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Zi-Cong Lin
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Lin-Na Wang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Rui-Hong Chen
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Jiu-Jie Yang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Ya-Ling Zeng
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Rui-Long Zhang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Bai-Xiong Huang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xiao-Yun Yun
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xuan-Ying Wang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Lin-Lin Song
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Jian-Hui Wu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xing-Xia Wang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xi Chen
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Wei Zhang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Hui-Miao Wang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Li-Qun Qu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Meng-Han Liu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Betty Yuen Kwan Law
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Vincent Kam Wai Wong
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
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18
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Wu X, Ju T, Li Z, Li J, Zhai X, Han K. Target-independent hybridization chain reaction-fluorescence resonance energy transfer for sensitive assay of ctDNA based on Cas12a. Anal Chim Acta 2023; 1261:341170. [PMID: 37147050 DOI: 10.1016/j.aca.2023.341170] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/13/2023] [Accepted: 03/31/2023] [Indexed: 05/07/2023]
Abstract
Circulating tumor DNA (ctDNA) is a noninvasive biomarker which offer valuable information for cancer diagnosis and prognosis. In this study, a target-independent fluorescent signal system, Hybridization chain reaction-Fluorescence resonance energy transfer (HCR-FRET) system, is designed and optimized. Combined with CRISPR/Cas12a system, a fluorescent biosensing protocol was developed for sensing assay of T790 M. When the target is absent, the initiator remains intact, opens the fuel hairpins and triggers the following HCR-FRET. At presence of the target, the Cas12a/crRNA binary complex specifically recognizes the target, and the Cas12a trans-cleavage activity is activated. As a result, the initiator is cleaved and subsequent HCR responses and FRET processes are attenuated. This method showed detection range from 1 pM to 400 pM with a detection limit of 316 fM. The target independent property of the HCR-FRET system endows this protocol a promising potential to transplant to the assay of other DNA target in parallel.
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Affiliation(s)
- Xuelan Wu
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China
| | - Ting Ju
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China
| | - Zeyang Li
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China
| | - Jingwen Li
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China
| | - Xingwei Zhai
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China
| | - Kun Han
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China.
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Lin LH, Chang KW, Cheng HW, Liu CJ. Identification of Somatic Mutations in Plasma Cell-Free DNA from Patients with Metastatic Oral Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:10408. [PMID: 37373553 DOI: 10.3390/ijms241210408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/01/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genes TTN, PLEC, SYNE1, and USH2A were most frequently mutated in OSCC, and known driver genes, including KMT2D, LRP1B, TRRAP, and FLNA, were also significantly and frequently mutated. Additionally, the novel mutated genes CCDC168, HMCN2, STARD9, and CRAMP1 were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were RORC, SLC49A3, and NUMBL. Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix-receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy.
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Affiliation(s)
- Li-Han Lin
- Department of Medical Research, MacKay Memorial Hospital No. 92, Sec. 2, Chung San N. Rd., Taipei 10449, Taiwan
| | - Kuo-Wei Chang
- Institute of Oral Biology, School of Dentistry, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei 11121, Taiwan
| | - Hui-Wen Cheng
- Department of Medical Research, MacKay Memorial Hospital No. 92, Sec. 2, Chung San N. Rd., Taipei 10449, Taiwan
| | - Chung-Ji Liu
- Department of Medical Research, MacKay Memorial Hospital No. 92, Sec. 2, Chung San N. Rd., Taipei 10449, Taiwan
- Institute of Oral Biology, School of Dentistry, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Oral and Maxillofacial Surgery, Taipei MacKay Memorial Hospital, Taipei 10449, Taiwan
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20
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Balasundaram A, Kumar S U, D TK, Anil Dedge A, R G, K SS, R S, C GPD. The targeted next-generation sequence revealed SMAD4, AKT1, and TP53 mutations from circulating cell-free DNA of breast cancer and its effect on protein structure - A computational approach. J Biomol Struct Dyn 2023; 41:15584-15597. [PMID: 37011004 DOI: 10.1080/07391102.2023.2191122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 03/06/2023] [Indexed: 04/04/2023]
Abstract
Breast cancer biomarkers that detect marginally advanced stages are still challenging. The detection of specific abnormalities, targeted therapy selection, prognosis, and monitoring of treatment effectiveness over time are all made possible by circulating free DNA (cfDNA) analysis. The proposed study will detect specific genetic abnormalities from the plasma cfDNA of a female breast cancer patient by sequencing a cancer-related gene panel (MGM455 - Oncotrack Ultima), including 56 theranostic genes (SNVs and small INDELs). Initially, we determined the pathogenicity of the observed mutations using PredictSNP, iStable, Align-GVGD, and ConSurf servers. As a next step, molecular dynamics (MD) was implemented to determine the functional significance of SMAD4 mutation (V465M). Lastly, the mutant gene relationships were examined using the Cytoscape plug-in GeneMANIA. Using ClueGO, we determined the gene's functional enrichment and integrative analysis. The structural characteristics of SMAD4 V465M protein by MD simulation analysis further demonstrated that the mutation was deleterious. The simulation showed that the native structure was more significantly altered by the SMAD4 (V465M) mutation. Our findings suggest that SMAD4 V465M mutation might be significantly associated with breast cancer, and other patient-found mutations (AKT1-E17K and TP53-R175H) are synergistically involved in the process of SMAD4 translocate to nuclease, which affects the target gene translation. Therefore, this combination of gene mutations could alter the TGF-β signaling pathway in BC. We further proposed that the SMAD4 protein loss may contribute to an aggressive phenotype by inhibiting the TGF-β signaling pathway. Thus, breast cancer's SMAD4 (V465M) mutation might increase their invasive and metastatic capabilities.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ambritha Balasundaram
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Udhaya Kumar S
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Thirumal Kumar D
- Meenakshi Academy of Higher Education and Research (Deemed to be University), Chennai, Tamil Nadu, India
| | - Aditi Anil Dedge
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Gnanasambandan R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Satish Srinivas K
- Department of Radiation Oncology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
| | - Siva R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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21
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Computational Simulation of Colorectal Cancer Biomarker Particle Mobility in a 3D Model. Molecules 2023; 28:molecules28020589. [PMID: 36677649 PMCID: PMC9865637 DOI: 10.3390/molecules28020589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
Even though some methods for the detection of colorectal cancer have been used clinically, most of the techniques used do not consider the in situ detection of colorectal cancer (CRC) biomarkers, which would favor in vivo real-time monitoring of the carcinogenesis process and consequent studies of the disease. In order to give a scientific and computational framework ideal for the evaluation of diagnosis techniques based on the early detection of biomarker molecules modeled as spherical particles from the computational point of view, a computational representation of the rectum, stool and biomarker particles was developed. As consequence of the transport of stool, there was a displacement of CRC biomarker particles that entered the system as a result of the cellular apoptosis processes in polyps with a length lower than 1 cm, reaching a maximum velocity of 3.47×10-3 m/s. The biomarkers studied showed trajectories distant to regions of the polyp of origin in 1 min of simulation. The research results show that the biomarker particles for CRC respond to the variations in the movements of the stool with trajectories and speeds that depend on the location of the injury, which will allow locating the regions with the highest possibilities of catching particles through in situ measurement instruments in the future.
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22
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Zhuang X, Qian J, Xia X, Wang Y, Wang H, Jing L, Zhang Y, Zhang Y. Serum circulating free DNA of syncytin-1 as a novel molecular marker for early diagnosis of non-small-cell lung cancer. Biomark Med 2022; 16:1259-1268. [PMID: 36861469 DOI: 10.2217/bmm-2022-0499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023] Open
Abstract
Background: Liquid biopsy has been receiving attention as an emerging detection technology in the clinical application of non-small-cell lung cancer (NSCLC). Methods: We quantified serum circulating free DNA (cfDNA) of syncytin-1 in 126 patients and 106 controls, analyzed the correlation of level with pathological parameters and explored diagnostic utility. Results: The cfDNA of syncytin-1 levels in NSCLC patients were higher than healthy controls (p < 0.0001). These levels were associated with smoking history (p = 0.0393). The area under the curve of cfDNA of syncytin-1 was 0.802, and combination of cfDNA of syncytin-1/cytokeratin 19 fragment antigen 21-1/carcinoembryonic antigen markers improved diagnostic efficiency. Conclusion: The cfDNA of syncytin-1 was detected in NSCLC patients and can be used as a novel molecular marker for early diagnosis.
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Affiliation(s)
- Xuewei Zhuang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Jingrong Qian
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Xiyan Xia
- Department of Microbial Immune, Jinan Vocational College of Nursing, Jinan, Shandong, 250102, China
| | - Yuanling Wang
- Department of Nursing, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Hongchun Wang
- Department of Clinical Laboratory, Shandong University Qilu Hospital, Jinan, Shandong, 250012, China
| | - Liping Jing
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Yanli Zhang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Yong Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
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Gibor U, Perry Z, Netz U, Kirshtein B, Mizrahi S, Czeiger D, Sebbag G, Douvdevani A. Circulating Cell-free DNA in Patients With Acute Biliary Pancreatitis: Association With Disease Markers and Prolonged Hospitalization Time-A Prospective Cohort Study. Ann Surg 2022; 276:e861-e867. [PMID: 33351491 DOI: 10.1097/sla.0000000000004679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To evaluate cfDNA as an indicator of pancreatitis severity. BACKGROUND Acute pancreatitis severity scores have limited proficiency, and are complex and challenging to use clinically. Elevation of circulating cfDNA concentration has been shown to be associated with hospital length of stay (LOS) and mortality. METHODS In a prospective study, cfDNA concentration was measured by a simple fluorometric test, at admission and for 2 consecutive days, in patients with acute biliary pancreatitis (ABP). Ranson and APACHE II scores were used as measures of pancreatitis severity. Hospital LOS and mortality were used as outcome measures. RESULTS Seventy-eight patients were included. Patients with severe disease according to Ranson's Criteria (n = 24) had elevated median admission cfDNA compared to patients with mild disease (n = 54, 2252ng/ml vs 1228 ng/ml, P < 0.05 ). Admission cfDNA levels correlated with Ranson and APACHE II scores and markers of bile duct obstruction. LOS did not differ between patients with mild and severe disease according to Ranson and APACHE II scores. Patients with cfDNA at 24 hours concentrations above the cutoff value of healthy patients (>850 ng/ml) had a significantly longer LOS compared to those with normal cfDNA levels ( P < 0.001 ). CONCLUSIONS cfDNA, measured by a rapid simple assay, proved a valuable early marker of severity in ABP with clear advantages for prediction of LOS over Ranson and APACHE II. Measurement of cfDNA has the potential to be an effective practical approach to predict the course of ABP and should be further evaluated in larger trials.
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Affiliation(s)
- Udit Gibor
- Department of Surgery A, Soroka University Medical Center, Beer Sheva, Israel
- Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Zvi Perry
- Department of Surgery A, Soroka University Medical Center, Beer Sheva, Israel
- Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Uri Netz
- Department of Surgery A, Soroka University Medical Center, Beer Sheva, Israel
- Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Boris Kirshtein
- Department of Surgery A, Soroka University Medical Center, Beer Sheva, Israel
- Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Solly Mizrahi
- Department of Surgery A, Soroka University Medical Center, Beer Sheva, Israel
- Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - David Czeiger
- Ben-Gurion University of the Negev, Beer Sheva, Israel
- Department of Surgery B, Soroka University Medical Center, Beer Sheva, Israel
| | - Gilbert Sebbag
- Ben-Gurion University of the Negev, Beer Sheva, Israel
- Department of Surgery B, Soroka University Medical Center, Beer Sheva, Israel
| | - Amos Douvdevani
- Ben-Gurion University of the Negev, Beer Sheva, Israel
- Department of Clinical Biochemistry and Pharmacology, Soroka University Medical Center, Beer Sheva, Israel
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24
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Herzog H, Dogan S, Aktas B, Nel I. Targeted Sequencing of Plasma-Derived vs. Urinary cfDNA from Patients with Triple-Negative Breast Cancer. Cancers (Basel) 2022; 14:4101. [PMID: 36077638 PMCID: PMC9454533 DOI: 10.3390/cancers14174101] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
In breast cancer, the genetic profiling of circulating cell-free DNA (cfDNA) from blood plasma was shown to have good potential for clinical use. In contrast, only a few studies were performed investigating urinary cfDNA. In this pilot study, we analyzed plasma-derived and matching urinary cfDNA samples obtained from 15 presurgical triple-negative breast cancer patients. We used a targeted next-generation sequencing approach to identify and compare genetic alterations in both body fluids. The cfDNA concentration was higher in urine compared to plasma, but there was no significant correlation between matched samples. Bioinformatical analysis revealed a total of 3339 somatic breast-cancer-related variants (VAF ≥ 3%), whereof 1222 vs. 2117 variants were found in plasma-derived vs. urinary cfDNA, respectively. Further, 431 shared variants were found in both body fluids. Throughout the cohort, the recovery rate of plasma-derived mutations in matching urinary cfDNA was 47% and even 63% for pathogenic variants only. The most frequently occurring pathogenic and likely pathogenic mutated genes were NF1, CHEK2, KMT2C and PTEN in both body fluids. Notably, a pathogenic CHEK2 (T519M) variant was found in all 30 samples. Taken together, our results indicated that body fluids appear to be valuable sources bearing complementary information regarding the genetic tumor profile.
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Affiliation(s)
- Henrike Herzog
- Department of Gynecology, Medical Center, University of Leipzig, 04103 Leipzig, Germany
| | - Senol Dogan
- Soft Matter Physics Division, Peter-Debye-Institute, University of Leipzig, 04103 Leipzig, Germany
| | - Bahriye Aktas
- Department of Gynecology, Medical Center, University of Leipzig, 04103 Leipzig, Germany
| | - Ivonne Nel
- Department of Gynecology, Medical Center, University of Leipzig, 04103 Leipzig, Germany
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25
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Ahmad E, Ali A, Nimisha, Kumar Sharma A, Apurva, Kumar A, Dar GM, Sumayya Abdul Sattar R, Verma R, Mahajan B, Singh Saluja S. Molecular markers in cancer. Clin Chim Acta 2022; 532:95-114. [DOI: https:/doi.org/10.1016/j.cca.2022.05.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
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26
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Ahmad E, Ali A, Nimisha, Kumar Sharma A, Apurva, Kumar A, Mehdi G, Sumayya Abdul Sattar R, Verma R, Mahajan B, Singh Saluja S. Molecular markers in cancer. Clin Chim Acta 2022; 532:95-114. [DOI: 10.1016/j.cca.2022.05.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 12/01/2022]
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Alese OB, Cook N, Ortega-Franco A, Ulanja MB, Tan L, Tie J. Circulating Tumor DNA: An Emerging Tool in Gastrointestinal Cancers. Am Soc Clin Oncol Educ Book 2022; 42:1-20. [PMID: 35471832 DOI: 10.1200/edbk_349143] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response-including for overall survival, progression-free survival, and disease-free survival-is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers-including tumors of the esophagus, stomach, colon, liver, and pancreas-account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.
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Affiliation(s)
- Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Natalie Cook
- Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom.,Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Ana Ortega-Franco
- Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mark B Ulanja
- Christus Ochsner St. Patrick Hospital, Lake Charles, LA
| | - Lavinia Tan
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Jeanne Tie
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.,Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
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28
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Triantafyllou A, Gazouli M, Theodoropoulos C, Zografos E, Zografos GC, Michalopoulos NV. Exosomes in breast cancer management: Where do we stand? A literature review. Biol Cell 2022; 114:109-122. [PMID: 35080041 DOI: 10.1111/boc.202100081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/10/2022] [Accepted: 01/17/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Exosomes constitute cellular molecular fingertips that participate in intercellular communication both in health and disease states. Hence, exosomes emerge as critical mediators of cancer development and progression, as well as potential biomarkers and novel therapeutic targets. OBJECTIVE To review literature data regarding applications of circulating exosomes in breast cancer management. METHODS This is a literature review of relevant published studies until April 2020 in PubMed and Google Scholar databases. Original papers in the English language concerning exosome related studies were included. RESULTS Exosomes represent molecular miniatures of their parent cells. Several homeostatic mechanisms control exosomal secretion and synthesis. Exosomal exchange among cells creates an intricate intercellular crosstalk orchestrating almost every tissue process, as well as carcinogenesis. Available data highlight exosomes as major mediators of cancer development and progression. The secretion of specific exosomal molecules, particularly miRNAs, correlates with the underlying processes and can be used as a means of tumor detection and prognostic assessment. CONCLUSIONS Exosomal miRNAs expression profiles and levels closely relate to cancer extent, type and prognosis. Deep comprehension of such correlations and systematization of experimental outcomes will offer a novel approach in cancer detection and management.
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Affiliation(s)
- Alexandra Triantafyllou
- 1st Propaedeutic Surgical Department, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Gazouli
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Charalampos Theodoropoulos
- 1st Propaedeutic Surgical Department, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Zografos
- 1st Propaedeutic Surgical Department, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George C Zografos
- 1st Propaedeutic Surgical Department, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos V Michalopoulos
- 1st Propaedeutic Surgical Department, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Al Sharhan NA, Messaoudi SA, Babu SR, Chaudhary AB, Alsharm AA, Alrefaei AF, Kadasah S, Abu-Elmagd M, Assidi M, Buhmeida A, Carracedo Á, Almawi WY. Utility of Circulating Cell-Free DNA in Assessing Microsatellite Instability and Loss of Heterozygosity in Breast Cancer Using Human Identification Approach. Genes (Basel) 2022; 13:590. [PMID: 35456396 PMCID: PMC9027523 DOI: 10.3390/genes13040590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
The diagnostic and prognostic utility of circulating cell-free DNA (cfDNA) in breast cancer (BC) patients was recently reported. Here, we investigated the use of cfDNA to examine microsatellite instability (MSI) and loss of heterozygosity (LOH) for early BC diagnosis. cfDNA and genomic DNA from 41 female BC patients and 40 healthy controls were quantified using NanoDrop spectrophotometry and real-time PCR. The stability of genomic and cfDNA was assessed using a high-resolution AmpFlSTR MiniFiler human identification kit. Significant increases in cfDNA plasma concentrations were observed in BC patients compared to controls. The genotype distribution of the eight autosomal short tandem repeat (STR) loci D7S820, D13S317, D21S11, D2S1338, D18S51, D16S539, FGA, and CSF1PO were in Hardy-Weinberg equilibrium. Significant differences in the allele frequencies of D7S820 allele-8, D21S11 allele-29, allele-30.2, allele-32.2, and CSF1PO allele-11 were seen between BC patients and controls. LOH and MSI were detected in 36.6% of the cfDNA of patients compared to genomic DNA. This study highlights the utility of plasma-derived cfDNA for earlier, less invasive, and cost-effective cancer diagnosis and molecular stratification. It also highlights the potential value of cfDNA in molecular profiling and biomarkers discovery in precision and forensic medicine.
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Affiliation(s)
- Norah A. Al Sharhan
- Department of Biopharmaceutical, Laboratories and Research Sector, Saudi Food and Drug Authority, Riyadh 3292, Saudi Arabia;
| | - Safia A. Messaoudi
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University for Security Sciences, Riyadh 14812, Saudi Arabia; (S.A.M.); (S.R.B.); (A.B.C.)
| | - Saranya R. Babu
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University for Security Sciences, Riyadh 14812, Saudi Arabia; (S.A.M.); (S.R.B.); (A.B.C.)
| | - AbdulRauf B. Chaudhary
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University for Security Sciences, Riyadh 14812, Saudi Arabia; (S.A.M.); (S.R.B.); (A.B.C.)
- Surgery Department, King Fahad Medical City, Riyadh 12231, Saudi Arabia
| | - Abdullah A. Alsharm
- Medical Oncology Department, King Fahad Medical City, Riyadh 12231, Saudi Arabia;
| | | | - Sultan Kadasah
- Department of Biology, Faculty of Sciences, University of Bisha, Bisha 61922, Saudi Arabia;
| | - Muhammad Abu-Elmagd
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.-E.); (M.A.); (A.B.)
- Medical Laboratory Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mourad Assidi
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.-E.); (M.A.); (A.B.)
- Medical Laboratory Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdelbaset Buhmeida
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.A.-E.); (M.A.); (A.B.)
| | - Ángel Carracedo
- Grupo de Medicina Xenómica, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), CIBERER, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Wassim Y. Almawi
- Faculté des Sciences de Tunis, Université de Tunis—El Manar, Tunis 1068, Tunisia
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30
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Mir IH, Jyothi KC, Thirunavukkarasu C. The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation. J Cell Biochem 2021; 123:1607-1623. [PMID: 34897788 DOI: 10.1002/jcb.30190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/13/2021] [Accepted: 11/17/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive and truculent types of cancer. Early detection of HCC is a massive concern that can boost the overall survival rates of HCC patients. As a result, there is a continual quest for advancements in screening, diagnosis, and treatment strategies to enhance the prognosis at its early stages. However, the confluence of inflammation and cirrhosis hampers the early detection of HCC. The analysis of different types of biomarkers such as tissue biomarkers, serum biomarkers, protein biomarkers, autoantibody markers, and improved imaging techniques has played a vital role in ameliorating HCC monitoring responses. Therefore biomarkers that can identify HCC early with a high degree of sensitivity and specificity might be prodigiously serviceable in the diagnosis and treatment of this notorious disorder. This study offers an overview of the contemporary understanding of several types of biomarkers implicated in hepatocarcinogenesis and their applications in monitoring, diagnosis, and prognosis presage. In additament, we address the role of image techniques associated with HCC diagnosis.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - K C Jyothi
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Virzì GM, Clementi A, Milan Manani S, Castellani C, Battaglia GG, Angelini A, Vescovo G, Ronco C. The Role of Cell-Free Plasma DNA in Patients with Cardiorenal Syndrome Type 1. Cardiorenal Med 2021; 11:218-225. [PMID: 34518452 DOI: 10.1159/000518553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/17/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. METHODS We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. RESULTS We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. CONCLUSION Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.
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Affiliation(s)
- Grazia Maria Virzì
- IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.,Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy
| | - Anna Clementi
- Department of Nephrology and Dialysis, Santa Marta and Santa Venera Hospital, Acireale, Italy
| | - Sabrina Milan Manani
- IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.,Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy
| | - Chiara Castellani
- Department of Medicine DIMED, University of Padua Medical School, Padua, Italy
| | | | - Annalisa Angelini
- Department of Medicine DIMED, University of Padua Medical School, Padua, Italy
| | - Giorgio Vescovo
- Internal Medicine, San Bortolo Hospital, Vicenza, Italy.,Internal Medicine Unit Sant'Antonio Hospital Padua, Padua, Italy
| | - Claudio Ronco
- IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.,Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy.,Department of Medicine DIMED, University of Padua Medical School, Padua, Italy
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32
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Guo K, Shao C, Han L, Liu H, Ma Z, Yang Y, Feng Y, Pan M, Santarpia M, Carmo-Fonseca M, Silveira C, Lee KY, Han J, Li X, Yan X. Detection of epidermal growth factor receptor ( EGFR) mutations from preoperative circulating tumor DNA (ctDNA) as a prognostic predictor for stage I-III non-small cell lung cancer (NSCLC) patients with baseline tissue EGFR mutations. Transl Lung Cancer Res 2021; 10:3213-3225. [PMID: 34430359 PMCID: PMC8350110 DOI: 10.21037/tlcr-21-530] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 07/19/2021] [Indexed: 12/24/2022]
Abstract
Background Plasma circulating tumor DNA (ctDNA) may be a surrogate, minimally invasive approach to tissue-based epidermal growth factor receptor (EGFR) mutation detection in non-small cell lung cancer (NSCLC) patients. However, the predictive ability of preoperative ctDNA EGFR mutation test on long-term postoperative survival and tumor metastasis development has not been extensively investigated. Methods Stage I–III NSCLC patients with tissue EGFR mutations were enrolled in this study (n=174). The ctDNA EGFR mutations were identified in paired preoperative plasma samples. EGFR mutation testing was performed using Scorpion amplified refractory mutation system (ARMS) technology. The correlation between ctDNA EGFR mutation status and clinicopathologic parameters was analyzed. By combining at least 5 years of follow-up data, we assessed the relationship between ctDNA EGFR mutation status and disease-free survival (DFS) and overall survival (OS). Results Plasma-based ctDNA EGFR mutations were detected in 27 patients. The mutation types were exactly matched with those in paired tissue samples. Blood test sensitivity was closely associated with N stages, tumor-node-metastasis (TNM) stages and tumor differentiation (P<0.001). The overall 5-year survival rate was 18.5% versus 76.9% for ctDNA EGFR mutation-positive and ctDNA EGFR mutation-negative patients, respectively. For patients with ctDNA EGFR mutation positive, the median OS and DFS were 29.00±2.55 and 19.00±2.50 months, respectively, which were both significantly better than those in the ctDNA EGFR mutation-negative subgroup (P<0.001). ctDNA EGFR mutation was an independent risk factor of OS and DFS [hazard ratio (HR) 3.289, 95% confidence interval (CI), 1.816–5.956, P<0.001; HR, 4.860, 95% CI, 2.660–8.880, P<0.001]. For stage III patients with exon 19 deletion or L858R mutations in both tissue and plasma samples, tyrosine kinase inhibitor (TKI) therapy showed significantly better OS (P=0.025) and possible DFS benefit (P=0.060) than did chemotherapy. Conclusions EGFR mutation testing using the Scorpion-ARMS method in preoperative plasma could be a strong predictor for postoperative survival and metastasis of NSCLC patients. Thus, the subset of this population may be benefit from targeted strategies and management.
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Affiliation(s)
- Kai Guo
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China.,Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, Xi'an, China.,The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Changjian Shao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Lu Han
- Department of Ultrasound, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Honggang Liu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Zhiqiang Ma
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Yang Yang
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Yingtong Feng
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Minghong Pan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Patology "G. Barresi", University of Messina, Messina, Italy
| | - Maria Carmo-Fonseca
- Instituto de Medicina Molecular João Lobo Antunes, University of Lisbon Medical School, Lisbon, Portugal
| | | | - Kye Young Lee
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea
| | - Jing Han
- Department of Ophthalmology, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, China
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Campos CDM, Childers K, Gamage SST, Wijerathne H, Zhao Z, Soper SA. Analytical Technologies for Liquid Biopsy of Subcellular Materials. ANNUAL REVIEW OF ANALYTICAL CHEMISTRY (PALO ALTO, CALIF.) 2021; 14:207-229. [PMID: 33974805 PMCID: PMC8601690 DOI: 10.1146/annurev-anchem-091520-093931] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Liquid biopsy markers, which can be secured from a simple blood draw or other biological samples, are used to manage a variety of diseases and even monitor for bacterial or viral infections. Although there are several different types of liquid biopsy markers, the subcellular ones, including cell-free DNA, microRNA, extracellular vesicles, and viral particles, are evolving in terms of their utility. A challenge with liquid biopsy markers is that they must be enriched from the biological sample prior to analysis because they are a vast minority in a mixed population, and potential interferences may be present in the sample matrix that can inhibit profiling the molecular cargo from the subcellular marker. In this article, we discuss existing and developing analytical enrichment platforms used to isolate subcellular liquid biopsy markers, and discuss their figures of merit such as recovery, throughput, and purity.
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Affiliation(s)
- Camila D M Campos
- Life Science Department, Imec, 3001 Leuven, Belgium
- Department of Electrical Engineering, KU Leuven, 3001 Leuven, Belgium
| | - Katie Childers
- Bioengineering Program, University of Kansas, Lawrence, Kansas 66045, USA;
- Center of BioModular Multiscale Systems for Precision Medicine, Lawrence, Kansas 66045, USA
| | - Sachindra S T Gamage
- Center of BioModular Multiscale Systems for Precision Medicine, Lawrence, Kansas 66045, USA
- Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, USA
| | - Harshani Wijerathne
- Department of Mechanical Engineering, Temple University, Philadelphia, Pennsylvania 19122, USA
| | - Zheng Zhao
- Bioengineering Program, University of Kansas, Lawrence, Kansas 66045, USA;
- Center of BioModular Multiscale Systems for Precision Medicine, Lawrence, Kansas 66045, USA
| | - Steven A Soper
- Bioengineering Program, University of Kansas, Lawrence, Kansas 66045, USA;
- Center of BioModular Multiscale Systems for Precision Medicine, Lawrence, Kansas 66045, USA
- Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, USA
- Department of Mechanical Engineering, University of Kansas, Lawrence, Kansas 66045, USA
- KU Cancer Center, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
- Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea
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Voss T, Ullius A, Schönborn M, Oelmüller U. Sensitivity assessment of workflows detecting rare circulating cell-free DNA targets: A study design proposal. PLoS One 2021; 16:e0253401. [PMID: 34228726 PMCID: PMC8260181 DOI: 10.1371/journal.pone.0253401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/03/2021] [Indexed: 11/18/2022] Open
Abstract
The field of liquid biopsy has seen extensive growth in recent decades, making it one of the most promising areas in molecular diagnostics. Circulating cell-free DNA (ccfDNA) especially is used as an analyte in a growing number of diagnostic assays. These assays require specified preanalytical workflows delivering ccfDNA in qualities and quantities that facilitate correct and reliable results. As each step and component used in the preanalytical process has the potential to influence the assay sensitivity and other performance characteristics, it is key to find an unbiased experimental setup to test these factors in diagnostic or research laboratories. We defined one such setup by using blood from healthy subjects and commercially available products for blood collection, spike-in material, ccfDNA isolation, and qPCR assays. As the primary read-out, we calculated the probit model-based LOD95 (limit of detection of the 95th percentile) from the qPCR assay results. In a proof of principle study we tested two different but widely used blood ccfDNA profile stabilization technologies in blood collection tubes, the Cell-Free DNA BCT and the PAXgene Blood ccfDNA Tube. We tested assays for three different EGFR gene mutations and one BRAF gene mutation. The study design revealed differences in performance between the two tested technologies for all four mutations. In conclusion, we successfully established a blueprint for a test procedure capable of verifying and validating a liquid biopsy workflow from blood collection to the analytical result.
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Affiliation(s)
- Thorsten Voss
- R&D Department, QIAGEN GmbH, Hilden, Germany
- * E-mail:
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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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Meng Z, Ren Q, Zhong G, Li S, Chen Y, Wu W, Feng Y, Mao M, Zhang F, Long G. Noninvasive Detection of Hepatocellular Carcinoma with Circulating Tumor DNA Features and α-Fetoprotein. J Mol Diagn 2021; 23:1174-1184. [PMID: 34182124 DOI: 10.1016/j.jmoldx.2021.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 04/27/2021] [Accepted: 06/08/2021] [Indexed: 01/05/2023] Open
Abstract
Liver cancer is the fifth-most common cancer worldwide, with the third-highest rate of cancer-related mortality. Hepatocellular carcinoma (HCC) is the leading pathologic subtype, contributing 85% to 90% of cases of primary liver cancer. Most HCC patients are diagnosed at an advanced stage at which treatment is not curative. This study assessed the performance of a newly developed blood-based assay that utilizes genomic features and protein markers for the early detection of HCC. Two cancer-associated hallmarks, copy-number aberrations (CNA) and fragment size (FS), were characterized by shallow whole-genome sequencing of cell-free DNA and utilized to differentiate cancer patients from healthy subjects. As a clinically implemented biomarker of HCC, plasma α-fetoprotein (AFP) was also used with the genomic surrogates to optimize the detection of HCCs. The sensitivity of AFP ≥20.0 μg/L in detecting HCC was 57.9%. The combined genomic classifier CNA + FS via cell-free DNA shallow whole-genome sequencing identified nearly half of AFP-negative HCC patients (43.8%). By integrating CNA, FS as well as AFP (HCCseek), 75.0% sensitivity was achieved at 98.0% specificity, resulting in 92.6% accuracy, with 58.6% sensitivity in stage I HCC. The quantitative output of HCCseek was correlated with the severity of the disease (tumor size, stage, and recurrence-free survival). In summary, this study describes an efficient, noninvasive, and cost-effective method to detect HCC.
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Affiliation(s)
- Zuowei Meng
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Qingqi Ren
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Guolin Zhong
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Shiyong Li
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Yan Chen
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Wei Wu
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Yumin Feng
- Research & Development, SeekIn Inc., Shenzhen, China
| | - Mao Mao
- Research & Development, SeekIn Inc., Shenzhen, China; Yonsei Song-Dang Institute for Cancer Research, Yonsei University, Seoul, Republic of Korea.
| | - Feng Zhang
- Research & Development, SeekIn Inc., Shenzhen, China.
| | - Guanghui Long
- Peking University Shenzhen Hospital, Shenzhen, China
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Li S, Zhang G, Li X, Li X, Chen X, Xu Y, Ren H. Role of the preoperative circulating tumor DNA KRAS mutation in patients with resectable pancreatic cancer. Pharmacogenomics 2021; 22:657-667. [PMID: 34120460 DOI: 10.2217/pgs-2020-0183] [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: 11/21/2022] Open
Abstract
Aim: The prognosis of resectable pancreatic cancer patients with the same stage of disease is highly variable. The purpose of this study is to establish a scoring system for preoperative screening of resectable patients. Materials & methods: The clinical information and laboratory tests of 105 resectable patients with pancreatic cancer were enrolled and analyzed. Results: The consistency of clinical stage and pathological stage was poor (κ = 0.193; p < 0.003). We performed a comprehensive scoring system with KRAS mutations in circulating tumor DNA (mutKRAS ctDNA) for the resectable patients. Patients with higher scores were more prone to early postoperative recurrence and poorer prognosis. Conclusion: The scoring system can help preoperatively screen out resectable patients who are prone to early postoperative recurrence.
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Affiliation(s)
- Shengnan Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Gengpu Zhang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xin Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiaojie Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - XiaoBing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yu Xu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Department of Oncology, Tianjin Huanghe Hospital, Tianjin, 300060, China
| | - He Ren
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.,Department of Gastroenterology, Center of Tumor Immunology & Cytotherapy, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
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Shen Z, Chen C, Sun J, Huang J, Liu S. The status of WIF1 methylation in cell-free DNA is associated with the insusceptibility for gefitinib in the treatment of lung cancer. J Cancer Res Clin Oncol 2021; 147:2239-2248. [PMID: 34037837 DOI: 10.1007/s00432-021-03640-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 04/10/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Targeted cancer therapy has shed light on the treatment of tumor, especially for patients with non-small cell lung cancer. However, only a limited portion of NSCLC patients carrying specific mutations showed an ideal drug response. In addition, DNA methylation status showed a great potential for cancer detection and prognosis prediction. METHODS Bisulfite sequencing was performed to analyze the DNA methylation of WIF1 promoter in cfDNA and tumor tissue samples collected from NSCLC patients. PFS and OS analyses were carried out to evaluate the prognosis of gefitinib treatment in patients with differential levels of WIF1 DNA methylation. Quantitative real-time PCR was used to analyze the expression of WIF1 mRNA, while immunohistochemistry was performed to assess the expression of WIF1 protein. Furthermore, ELISA was carried out to evaluate the WIF1 activity in plasma. RESULTS The DNA methylation level of WIF1 promoter was lower in the cfDNA of NSCLC patients with a complete or partial response to gefitinib, and NSCLC patients with hypomethylated WIF1 showed better PFS and OS. The DNA methylation of WIF1 promoter in the resected tumor tissues was consistent with WIF1 DNA methylation in cfDNA, indicating that cfDNA was mainly derived from lung cancer tissues. As a result, the expression of WIF1 in tissue samples and the WIF1 activity in plasma was inhibited in patients with hypermethylated WIF1. Moreover, the cell viability of gefitinib-resistant cells was decreased by the suppressed WIF1 methylation in vitro. And the expression level of WIF1 mRNA was higher in gefitinib-resistant cells overexpressing ALKBH5, a known suppressor of WIF1 methylation. CONCLUSION In summary, the findings of this study demonstrated that the level of WIF1 methylation in cfDNA was associated with the insusceptibility of gefitinib in the treatment of lung cancer.
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Affiliation(s)
- Zhijun Shen
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.,Department of Clinical Laboratory, Hubei No. 3 People's Hospital of Jianghan University, No. 26 Zhongshan Avenue, Wuhan, 430033, Hubei, China
| | - Chen Chen
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Jianhai Sun
- Department of Oncology, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, 430033, Hubei, China
| | - Jingsong Huang
- Department of Transfusion, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, 361101, Fujian, China.
| | - Shiguo Liu
- Department of Clinical Laboratory, Hubei No. 3 People's Hospital of Jianghan University, No. 26 Zhongshan Avenue, Wuhan, 430033, Hubei, China.
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Stance of MRD in Non-Hodgkin's Lymphoma and its upsurge in the novel era of cell-free DNA. Clin Transl Oncol 2021; 23:2206-2219. [PMID: 33991328 DOI: 10.1007/s12094-021-02635-4] [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: 02/12/2021] [Accepted: 05/02/2021] [Indexed: 10/21/2022]
Abstract
Cancer genomics has evolved over the years from understanding the pathogenesis of cancer to screening the future possibilities of cancer occurrence. Understanding the genetic profile of tumors holds a prognostic as well as a predictive value in this era of therapeutic surveillance, molecular remission, and precision medicine. Identifying molecular markers in tumors is the current standard of approach, and requires an efficient combination of an accessible sample type and a profoundly sensitive technique. Liquid biopsy or cell-free DNA has evolved as a novel sample type with promising results in recent years. Although cell-free DNA has significant role in various cancer types, this review focuses on its application in Non-Hodgkin's Lymphoma. Beginning with the current concept and clinical relevance of minimal residual disease in Non-Hodgkin's lymphoma, we discuss the literature on circulating DNA and its evolving application in the realm of cutting-edge technology.
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Rabber L, Ernest T, Miller Gelkop Y, Cohen Lahav M, Douvdevani A, Nahum A. Fast fluorometric method for measuring circulating cell-free DNA could aid the diagnosis of febrile children. Acta Paediatr 2021; 110:1577-1578. [PMID: 33222298 DOI: 10.1111/apa.15680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 11/28/2022]
Affiliation(s)
- Liron Rabber
- Pediatrics Department A Soroka University Medical Center Beer Sheva Israel
| | - Tal‐El Ernest
- Pediatrics Department A Soroka University Medical Center Beer Sheva Israel
| | - Yael Miller Gelkop
- Department of Clinical Biochemistry and Pharmacology Soroka University Medical Center Ben‐Gurion University of the Negev Beer‐Sheva Israel
| | - Merav Cohen Lahav
- Division of Laboratories Soroka University Medical Center Beer‐Sheva Israel
| | - Amos Douvdevani
- Department of Clinical Biochemistry and Pharmacology Soroka University Medical Center Ben‐Gurion University of the Negev Beer‐Sheva Israel
| | - Amit Nahum
- Pediatrics Department A Soroka University Medical Center Beer Sheva Israel
- The Primary Immunodeficiency Research Laboratory Faculty of Health Sciences Ben‐Gurion University of the Negev Beer‐Sheva Israel
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Colmer SF, Luethy D, Abraham M, Stefanovski D, Hurcombe SD. Utility of cell-free DNA concentrations and illness severity scores to predict survival in critically ill neonatal foals. PLoS One 2021; 16:e0242635. [PMID: 33901192 PMCID: PMC8075268 DOI: 10.1371/journal.pone.0242635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 04/13/2021] [Indexed: 11/18/2022] Open
Abstract
Plasma cell-free DNA (cfDNA) levels have been associated with disease and survival status in septic humans and dogs. To date, studies investigating cfDNA levels in association with critical illness in foals are lacking. We hypothesized that cfDNA would be detectable in the plasma of foals, that septic and sick-nonseptic foals would have significantly higher cfDNA levels compared to healthy foals, and that increased cfDNA levels would be associated with non-survival. Animals used include 80 foals of 10 days of age or less admitted to a tertiary referral center between January and July, 2020 were stratified into three categories: healthy (n = 34), sick non-septic (n = 11) and septic (n = 35) based on specific criteria. This was a prospective clinical study. Blood was collected from critically ill foals at admission or born in hospital for cfDNA quantification and blood culture. Previously published sepsis score (SS) and neonatal SIRS score (NSIRS) were also calculated. SS, NSIRS, blood culture status and cfDNA concentrations were evaluated to predict survival. Continuous variables between groups were compared using Kruskal-Wallis ANOVA with Dunn’s post hoc test. Comparisons between two groups were assessed using the Mann-Whitney U-test or Spearman rank for correlations. The performance of cfDNA, sepsis score and NSIRS score to predict survival was assessed by receiver operator characteristic (ROC) curve analysis including area under the curve, sensitivity and specificity using cutoffs. Plasma cfDNA was detectable in all foals. No significant differences in cfDNA concentration were detected between healthy foals and septic foals (P = 0.65) or healthy foals and sick non-septic foals (P = 0.88). There was no significant association between cfDNA and culture status, SS, NSIRS or foal survival. SS (AUC 0.85) and NSIRS (AUC 0.83) were superior to cfDNA (AUC 0.64) in predicting survival. Although cfDNA was detectable in foal plasma, it offers negligible utility to diagnose sepsis or predict survival in critical illness in neonates.
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Affiliation(s)
- Sarah Florence Colmer
- Department of Clinical Sciences, The University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Philadelphia, Pennsylvania, United States of America
| | - Daniela Luethy
- Department of Clinical Sciences, The University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Philadelphia, Pennsylvania, United States of America
| | - Michelle Abraham
- Department of Clinical Sciences, The University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Philadelphia, Pennsylvania, United States of America
| | - Darko Stefanovski
- Department of Clinical Sciences, The University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Philadelphia, Pennsylvania, United States of America
| | - Samuel David Hurcombe
- Department of Clinical Sciences, The University of Pennsylvania School of Veterinary Medicine, New Bolton Center, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival. Cancers (Basel) 2021; 13:cancers13071612. [PMID: 33807330 PMCID: PMC8038004 DOI: 10.3390/cancers13071612] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/27/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. KRAS mutations occur in up to 95% of cases and render the tumor resistant to many types of therapy. Therefore, these patients are treated with traditional cytotoxic agents, according to guidelines. The familial or hereditary form of the disease accounts for up to 10–15% of cases. We hypothesized that hereditary and Familial Pancreatic Cancer cases (H/FPC) have a distinct tumor specific mutation profile due to the presence of pathogenic germline mutations and we used circulating free DNA (cfDNA) in plasma to assess this hypothesis. H/FPC cases were mainly KRAS mutation negative and harbored tumor specific mutations that are potential treatment targets in the clinic. Thus, we conclude that cases with a hereditary or familial background can be treated with newer and more effective agents that may ultimately improve their overall survival. Abstract Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.
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de Souza Barbosa Ê, Santos Ibiapina HN, Rocha da Silva S, Costa AG, Val FF, Mendonça-da-Silva I, Carlos de Lima Ferreira L, Sartim MA, Monteiro WM, Cardoso de Melo G, de Almeida Gonçalves Sachett J. Association of cfDNA levels and bothrops envenomation. Toxicon 2021; 192:66-73. [PMID: 33497746 DOI: 10.1016/j.toxicon.2021.01.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/21/2020] [Accepted: 01/20/2021] [Indexed: 01/05/2023]
Abstract
In the Amazon, around 90% of snakebites are caused by the Bothrops genus. Complications arising from Bothrops envenomations result from the inflammatory and coagulotoxic activities of the venom. The aim of this study was to investigate the potential of cell-free DNA (cfDNA) as a biomarker of severity in Bothrops snakebites. Patients were treated at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, in the Brazilian Amazon. cfDNA plasma levels were measured by amplifying the human telomerase reverse transcriptase (hTERT) sequence using quantitative RT-PCR. Median levels of cfDNA were compared between envenomed and healthy volunteers and among patients presenting different complications, such as renal failure, bleeding and infection. Of the 76 patients included, 82.9% were male, with a mean age of 32.8 years, and envenomations were mainly classified as severe (39.5%). ROC curve analysis showed a good accuracy of cfDNA levels (AUROC of 0.745) in envenomation diagnosis. A correlation analysis using laboratory variables showed positive correlation with lactate dehydrogenase (p = 0.033) and platelet count (p = 0.003). When cfDNA levels were compared with clinical complications, significant statistical differences were only found among individuals with mild and severe pain (p < 0.05). In summary, our results demonstrated that cfDNA levels are sufficiently accurate for discriminating between envenomed and non-envenomed patients, but are not able to distinguish different complications and the level of severity among envenomed patients. Thus, the role of cfDNA in the pathogenesis of the snakebite envenomations needs to be further investigated.
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Affiliation(s)
- Êndila de Souza Barbosa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Hiochelson Najibe Santos Ibiapina
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | | | - Allyson Guimarães Costa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Fernando Fonseca Val
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Iran Mendonça-da-Silva
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Luiz Carlos de Lima Ferreira
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Faculdade de Medicina, Universidade Federal do Amazonas, Manaus, Brazil
| | - Marco Aurélio Sartim
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
| | - Wuelton Marcelo Monteiro
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Gisely Cardoso de Melo
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Jacqueline de Almeida Gonçalves Sachett
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Alfredo da Matta, Manaus, Brazil.
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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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Khomiak A, Brunner M, Kordes M, Lindblad S, Miksch RC, Öhlund D, Regel I. Recent Discoveries of Diagnostic, Prognostic and Predictive Biomarkers for Pancreatic Cancer. Cancers (Basel) 2020; 12:E3234. [PMID: 33147766 PMCID: PMC7692691 DOI: 10.3390/cancers12113234] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union with a five-year survival rate of below 9%. Surgical resection, followed by adjuvant chemotherapy, remains the only potentially curative treatment but only a minority of patients is diagnosed with locally resectable, non-metastatic disease. Patients with advanced disease are treated with chemotherapy but high rates of treatment resistance and unfavorable side-effect profiles of some of the used regimens remain major challenges. Biomarkers reflect pathophysiological or physiological processes linked to a disease and can be used as diagnostic, prognostic and predictive tools. Thus, accurate biomarkers can allow for better patient stratification and guide therapy choices. Currently, the only broadly used biomarker for PDAC, CA 19-9, has multiple limitations and the need for novel biomarkers is urgent. In this review, we highlight the current situation, recent discoveries and developments in the field of biomarkers of PDAC and their potential clinical applications.
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Affiliation(s)
- Andrii Khomiak
- Shalimov National Institute of Surgery and Transplantology, 03058 Kyiv, Ukraine;
| | - Marius Brunner
- Department of Gastroenterology, Endocrinology and Gastrointestinal Oncology, University Medical Center, 37075 Goettingen, Germany;
| | - Maximilian Kordes
- Department of Upper Abdominal Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden;
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 17177 Stockholm, Sweden
| | - Stina Lindblad
- Department of Radiation Sciences, Sweden and Wallenberg Centre for Molecular Medicine, Umeå University, 90187 Umeå, Sweden;
| | - Rainer Christoph Miksch
- Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, 81377 Munich, Germany;
| | - Daniel Öhlund
- Department of Radiation Sciences, Sweden and Wallenberg Centre for Molecular Medicine, Umeå University, 90187 Umeå, Sweden;
| | - Ivonne Regel
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
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Abstract
BACKGROUND Clinical application of immune checkpoint inhibitors (ICI), whether as monotherapy or in combination with established methods, is revolutionizing treatment of head and neck cancer. However, this change in therapeutic concepts requires reevaluation and further development of predictive and prognostic markers, since the survival rates for advanced and particularly human papillomavirus (HPV)-negative disease remain poor. MATERIALS AND METHODS A selective literature review was performed in PubMed. Literature found with the keywords "cytodiagnostics, circulating tumor cells, liquid biopsy, cfDNA, exosomes" in combination with "head and neck cancer" and/or "immune checkpoint inhibitor therapy" published until March 2020 was included. The articles were selected for their relevance for the current study by the authors. RESULTS This work provides a review of the current literature and indicates possible applications in the field of head and neck cancers. Liquid biopsy refers to the analysis of circulating tumor cells or of tumor genetic material in body fluids. This minimally invasive analysis can support therapeutic decisions and enable a personalized approach to treating head and neck cancer. DISCUSSION Before any of these approaches can be established in clinical routine, long-term data and standardization of the methods for isolating and analyzing the markers are needed.
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Plasma Cell-Free Human Papillomavirus Oncogene E6 and E7 DNA Predicts Outcome in Oropharyngeal Squamous Cell Carcinoma. J Mol Diagn 2020; 22:1333-1343. [PMID: 32822851 DOI: 10.1016/j.jmoldx.2020.08.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 12/24/2022] Open
Abstract
Persistent human papillomavirus (HPV) infection is associated with the development of oropharyngeal squamous cell carcinoma (OPSCC), and increasing incidences of OPSCC are reported. The generally favorable treatment outcome in patients with HPV-driven OPSCC has brought de-escalation of treatment into discussion. Nevertheless, 13% to 25% develop a relapse within two years after current standard treatment. New biomarkers are urgently required to monitor therapy response, tumor burden, and minimal residual disease during follow-up. This observational study examined 50 patients with OPSCC to investigate plasma cell-free (cf) HPV-DNA derived from tumor cells before therapy and during follow-up. Real-time PCR was applied to quantify the DNA concentration of HPV oncogenes E6 and E7. A total of 85.7% of pretreatment samples from patients with HPV-driven OPSCC (n = 28) were positive for at least one marker, and cfHPV-DNA concentration increased with tumor size. Virtually no signals were detected in HPV-negative OPSCC patients (n = 20; P ≤ 0.001). Patients without clinical evidence of recurrence had significantly reduced cfHPV-DNA concentrations after therapy (P ≤ 0.001). Conversely, cfHPV-DNA levels increased or remained above threshold in five patients who had residual disease or developed recurrence. In conclusion, plasma cfHPV-DNA detection correlates with the clinical course of disease in patients with HPV-driven OPSCC. Consequently, extensive clinical investigation should be considered if cfHPV-DNA is detected during follow-up of patients with HPV-driven OPSCC.
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Ponti G, Maccaferri M, Percesepe A, Tomasi A, Ozben T. Liquid biopsy with cell free DNA: new horizons for prostate cancer. Crit Rev Clin Lab Sci 2020; 58:60-76. [PMID: 32805148 DOI: 10.1080/10408363.2020.1803789] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Although prostate cancer (PCa) is one of the most common tumors in European males, the only minimally invasive diagnostic tool in PCa setup is the determination of PSA in serum. Cell-free DNA (cfDNA) has been demonstrated to be helpful for PCa diagnosis but has not yet been integrated into the clinical setting. This review aims to provide a systematic update of cfDNA and its fragmentation patterns in PCa reported in literature published over the last twenty years. Due to the high variability of the scientific methods adopted and a lack of standardized median cfDNA levels, results fluctuate across different studies. These differences may be due to the cfDNA source, the quantification method, or the fragmentation pattern. Blood plasma is the most frequently analyzed biological fluid, but seminal plasma has been reported to contain higher cfDNA concentration due to its vicinity to the tumor origin. CfDNA has been shown to be composed of single-stranded (ssDNA) and double-stranded DNA (dsDNA), so the total cfDNA concentration should be preferred as it corresponds best to the tumor mass. Fluorometry and capillary electrophoresis (CE) may be quick and cost-effective tools for cfDNA assessment in a clinical setting. The greatest future challenge is the elaboration of common guidelines and standardized procedures for diagnostic laboratories performing cfDNA analysis. A multiparametric approach combining the analysis of total cfDNA (both ssDNA and dsDNA), cfDNA fragment length, and specific genetic mutations (ctDNA assessment) is required for optimal future applications of liquid biopsy.
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Affiliation(s)
- Giovanni Ponti
- Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Monia Maccaferri
- Dermatology Unit, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy
| | - Antonio Percesepe
- Medical Genetics Unit, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Aldo Tomasi
- Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Tomris Ozben
- Faculty of Medicine, Department of Clinical Biochemistry, Akdeniz University, Antalya, Turkey
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Heredia FL, Resto PJ, Parés-Matos EI. Fast Adhesion of Gold Nanoparticles (AuNPs) to a Surface Using Starch Hydrogels for Characterization of Biomolecules in Biosensor Applications. BIOSENSORS 2020; 10:E99. [PMID: 32824022 PMCID: PMC7460011 DOI: 10.3390/bios10080099] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 11/17/2022]
Abstract
Gold nanoparticles (AuNPs) are the most thoroughly studied nanoparticles because of their remarkable optical properties. Color changes in assays that use AuNPs can be easily observed with the naked eye, resulting in sensitive colorimetric methods, useful for detecting a variety of biological molecules. However, while AuNPs represent an excellent nano-platform for developing analytical methods for biosensing, there are still challenges that must be overcome before colloidal AuNPs formulation can be successfully translated into practical applications. One of those challenges is the ability to immobilize AuNPs in a solid support. There are many difficulties with controlling both the cluster size and the adhesion of the coatings formed. In addition, many of the techniques employed are expensive and time-consuming, or require special equipment. Thus, a simple and inexpensive method that only requires common lab equipment for immobilizing AuNPs on a surface using Starch Hydrogels has been developed. Starch hydrogels confer a 400% increase in stability to the nanoparticles when exposed to changes in the environment while also allowing for macromolecules to interact with the AuNPs surface. Several starch derivatives were tested, including, dextrin, beta-cyclodextrin and maltodextrin, being dextrin the one that conferred the highest stability. As a proof-of-concept, a SlipChip microfluidic sensor scheme was developed to measure the concentration of DNA in a sample. The detection limit of our biosensor was found to be 25 ng/mL and 75 ng/mL for instrument and naked eye detection, respectively.
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Affiliation(s)
- Frances L. Heredia
- Department of Chemistry, University of Puerto Rico at Mayagüez, Mayagüez, PR 00680, USA;
| | - Pedro J. Resto
- Department of Mechanical Engineering, University of Puerto Rico at Mayagüez, Mayagüez, PR 00680, USA;
| | - Elsie I. Parés-Matos
- Department of Chemistry, University of Puerto Rico at Mayagüez, Mayagüez, PR 00680, USA;
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Wang T, Zhang KH. New Blood Biomarkers for the Diagnosis of AFP-Negative Hepatocellular Carcinoma. Front Oncol 2020; 10:1316. [PMID: 32923383 PMCID: PMC7456927 DOI: 10.3389/fonc.2020.01316] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/24/2020] [Indexed: 12/18/2022] Open
Abstract
An early diagnosis of hepatocellular carcinoma (HCC) followed by effective treatment is currently critical for improving the prognosis and reducing the associated economic burden. Alpha-fetoprotein (AFP) is the most widely used biomarker for HCC diagnosis. Based on elevated serum AFP levels as well as typical imaging features, AFP-positive HCC (APHC) can be easily diagnosed, but AFP-negative HCC (ANHC) is not easily detected due to lack of ideal biomarkers and thus mainly reliance on imaging. Imaging for the diagnosis of ANHC is probably insufficient in sensitivity and/or specificity because most ANHC tumors are small and early-stage HCC, and it is involved in sophisticated techniques and high costs. Moreover, ANHC accounts for nearly half of HCC and exhibits a better prognosis compared with APHC. Therefore, the diagnosis of ANHC in clinical practice has been a critical issue for the early treatment and prognosis improvement of HCC. In recent years, tremendous efforts have been made to discover new biomarkers complementary to AFP for HCC diagnosis. In this review, we systematically review and discuss the recent advances of blood biomarkers for HCC diagnosis, including DNA biomarkers, RNA biomarkers, protein biomarkers, and conventional laboratory metrics, focusing on their diagnostic evaluation alone and in combination, in particular on their diagnostic performance for ANHC.
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Affiliation(s)
- Ting Wang
- Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kun-He Zhang
- Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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