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Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection

SIMPLE SUMMARY: Prostate cancer occurs in one out of six men during their lifetime. Because its symptoms are not specific, it is often diagnosed late. The widely used prostate-specific antigen (PSA) blood test does not have sufficient accuracy, resulting in numerous unnecessary prostate biopsies in...

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Autores principales: Pchejetski, Dmitri, Hunter, Ewan, Dezfouli, Mehrnoush, Salter, Matthew, Powell, Ryan, Green, Jayne, Naithani, Tarun, Koutsothanasi, Christina, Alshaker, Heba, Jaipuria, Jiten, Connor, Martin J., Eldred-Evans, David, Fiorentino, Francesca, Ahmed, Hashim, Akoulitchev, Alexandre, Winkler, Mathias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913359/
https://www.ncbi.nlm.nih.gov/pubmed/36765779
http://dx.doi.org/10.3390/cancers15030821
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author Pchejetski, Dmitri
Hunter, Ewan
Dezfouli, Mehrnoush
Salter, Matthew
Powell, Ryan
Green, Jayne
Naithani, Tarun
Koutsothanasi, Christina
Alshaker, Heba
Jaipuria, Jiten
Connor, Martin J.
Eldred-Evans, David
Fiorentino, Francesca
Ahmed, Hashim
Akoulitchev, Alexandre
Winkler, Mathias
author_facet Pchejetski, Dmitri
Hunter, Ewan
Dezfouli, Mehrnoush
Salter, Matthew
Powell, Ryan
Green, Jayne
Naithani, Tarun
Koutsothanasi, Christina
Alshaker, Heba
Jaipuria, Jiten
Connor, Martin J.
Eldred-Evans, David
Fiorentino, Francesca
Ahmed, Hashim
Akoulitchev, Alexandre
Winkler, Mathias
author_sort Pchejetski, Dmitri
collection PubMed
description SIMPLE SUMMARY: Prostate cancer occurs in one out of six men during their lifetime. Because its symptoms are not specific, it is often diagnosed late. The widely used prostate-specific antigen (PSA) blood test does not have sufficient accuracy, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with cancer. We have recently developed an epigenetic test for prostate cancer that detects cancer-specific chromosome conformations in the blood of the patient. In this study, we combined this epigenetic test with the PSA test and used two cohorts of patients to determine whether they have better diagnostic accuracy when used together. Our results demonstrate that the new combined test (termed PSE test) allows significant increase in prostate cancer detection compared to PSA or epigenetic test alone. This new PSE test is accurate, rapid, minimally invasive, and inexpensive. If successful in larger trials, it may significantly improve prostate cancer diagnosis. ABSTRACT: Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch(®) PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.92 and NPV of 0.94 when tested on the independent prospective cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening.
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spelling pubmed-99133592023-02-11 Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection Pchejetski, Dmitri Hunter, Ewan Dezfouli, Mehrnoush Salter, Matthew Powell, Ryan Green, Jayne Naithani, Tarun Koutsothanasi, Christina Alshaker, Heba Jaipuria, Jiten Connor, Martin J. Eldred-Evans, David Fiorentino, Francesca Ahmed, Hashim Akoulitchev, Alexandre Winkler, Mathias Cancers (Basel) Article SIMPLE SUMMARY: Prostate cancer occurs in one out of six men during their lifetime. Because its symptoms are not specific, it is often diagnosed late. The widely used prostate-specific antigen (PSA) blood test does not have sufficient accuracy, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with cancer. We have recently developed an epigenetic test for prostate cancer that detects cancer-specific chromosome conformations in the blood of the patient. In this study, we combined this epigenetic test with the PSA test and used two cohorts of patients to determine whether they have better diagnostic accuracy when used together. Our results demonstrate that the new combined test (termed PSE test) allows significant increase in prostate cancer detection compared to PSA or epigenetic test alone. This new PSE test is accurate, rapid, minimally invasive, and inexpensive. If successful in larger trials, it may significantly improve prostate cancer diagnosis. ABSTRACT: Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch(®) PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.92 and NPV of 0.94 when tested on the independent prospective cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening. MDPI 2023-01-29 /pmc/articles/PMC9913359/ /pubmed/36765779 http://dx.doi.org/10.3390/cancers15030821 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pchejetski, Dmitri
Hunter, Ewan
Dezfouli, Mehrnoush
Salter, Matthew
Powell, Ryan
Green, Jayne
Naithani, Tarun
Koutsothanasi, Christina
Alshaker, Heba
Jaipuria, Jiten
Connor, Martin J.
Eldred-Evans, David
Fiorentino, Francesca
Ahmed, Hashim
Akoulitchev, Alexandre
Winkler, Mathias
Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title_full Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title_fullStr Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title_full_unstemmed Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title_short Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
title_sort circulating chromosome conformation signatures significantly enhance psa positive predicting value and overall accuracy for prostate cancer detection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913359/
https://www.ncbi.nlm.nih.gov/pubmed/36765779
http://dx.doi.org/10.3390/cancers15030821
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