Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients

Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Ariane Hallermayr [verfasserIn] Tobias Wohlfrom [verfasserIn] Verena Steinke-Lange [verfasserIn] Anna Benet-Pagès [verfasserIn] Florentine Scharf [verfasserIn] Ellen Heitzer [verfasserIn] Ulrich Mansmann [verfasserIn] Christopher Haberl [verfasserIn] Maike de Wit [verfasserIn] Holger Vogelsang [verfasserIn] Markus Rentsch [verfasserIn] Elke Holinski-Feder [verfasserIn] Julia M. A. Pickl [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation

Übergeordnetes Werk:	In: Journal of Hematology & Oncology - BMC, 2008, 15(2022), 1, Seite 14
Übergeordnetes Werk:	volume:15 ; year:2022 ; number:1 ; pages:14

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13045-022-01342-z

Katalog-ID:	DOAJ085117358

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520			\|a Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890.
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allfields	10.1186/s13045-022-01342-z doi (DE-627)DOAJ085117358 (DE-599)DOAJ0efaedafd6e94b90ae2a7a9642900c92 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Ariane Hallermayr verfasserin aut Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tobias Wohlfrom verfasserin aut Verena Steinke-Lange verfasserin aut Anna Benet-Pagès verfasserin aut Florentine Scharf verfasserin aut Ellen Heitzer verfasserin aut Ulrich Mansmann verfasserin aut Christopher Haberl verfasserin aut Maike de Wit verfasserin aut Holger Vogelsang verfasserin aut Markus Rentsch verfasserin aut Elke Holinski-Feder verfasserin aut Julia M. A. Pickl verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 14 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:14 https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/article/0efaedafd6e94b90ae2a7a9642900c92 kostenfrei https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2022 1 14
spelling	10.1186/s13045-022-01342-z doi (DE-627)DOAJ085117358 (DE-599)DOAJ0efaedafd6e94b90ae2a7a9642900c92 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Ariane Hallermayr verfasserin aut Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tobias Wohlfrom verfasserin aut Verena Steinke-Lange verfasserin aut Anna Benet-Pagès verfasserin aut Florentine Scharf verfasserin aut Ellen Heitzer verfasserin aut Ulrich Mansmann verfasserin aut Christopher Haberl verfasserin aut Maike de Wit verfasserin aut Holger Vogelsang verfasserin aut Markus Rentsch verfasserin aut Elke Holinski-Feder verfasserin aut Julia M. A. Pickl verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 14 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:14 https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/article/0efaedafd6e94b90ae2a7a9642900c92 kostenfrei https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2022 1 14
allfields_unstemmed	10.1186/s13045-022-01342-z doi (DE-627)DOAJ085117358 (DE-599)DOAJ0efaedafd6e94b90ae2a7a9642900c92 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Ariane Hallermayr verfasserin aut Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tobias Wohlfrom verfasserin aut Verena Steinke-Lange verfasserin aut Anna Benet-Pagès verfasserin aut Florentine Scharf verfasserin aut Ellen Heitzer verfasserin aut Ulrich Mansmann verfasserin aut Christopher Haberl verfasserin aut Maike de Wit verfasserin aut Holger Vogelsang verfasserin aut Markus Rentsch verfasserin aut Elke Holinski-Feder verfasserin aut Julia M. A. Pickl verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 14 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:14 https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/article/0efaedafd6e94b90ae2a7a9642900c92 kostenfrei https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2022 1 14
allfieldsGer	10.1186/s13045-022-01342-z doi (DE-627)DOAJ085117358 (DE-599)DOAJ0efaedafd6e94b90ae2a7a9642900c92 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Ariane Hallermayr verfasserin aut Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tobias Wohlfrom verfasserin aut Verena Steinke-Lange verfasserin aut Anna Benet-Pagès verfasserin aut Florentine Scharf verfasserin aut Ellen Heitzer verfasserin aut Ulrich Mansmann verfasserin aut Christopher Haberl verfasserin aut Maike de Wit verfasserin aut Holger Vogelsang verfasserin aut Markus Rentsch verfasserin aut Elke Holinski-Feder verfasserin aut Julia M. A. Pickl verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 14 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:14 https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/article/0efaedafd6e94b90ae2a7a9642900c92 kostenfrei https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2022 1 14
allfieldsSound	10.1186/s13045-022-01342-z doi (DE-627)DOAJ085117358 (DE-599)DOAJ0efaedafd6e94b90ae2a7a9642900c92 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Ariane Hallermayr verfasserin aut Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tobias Wohlfrom verfasserin aut Verena Steinke-Lange verfasserin aut Anna Benet-Pagès verfasserin aut Florentine Scharf verfasserin aut Ellen Heitzer verfasserin aut Ulrich Mansmann verfasserin aut Christopher Haberl verfasserin aut Maike de Wit verfasserin aut Holger Vogelsang verfasserin aut Markus Rentsch verfasserin aut Elke Holinski-Feder verfasserin aut Julia M. A. Pickl verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 14 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:14 https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/article/0efaedafd6e94b90ae2a7a9642900c92 kostenfrei https://doi.org/10.1186/s13045-022-01342-z kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2022 1 14
language	English
source	In Journal of Hematology & Oncology 15(2022), 1, Seite 14 volume:15 year:2022 number:1 pages:14
sourceStr	In Journal of Hematology & Oncology 15(2022), 1, Seite 14 volume:15 year:2022 number:1 pages:14
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Journal of Hematology & Oncology
authorswithroles_txt_mv	Ariane Hallermayr @@aut@@ Tobias Wohlfrom @@aut@@ Verena Steinke-Lange @@aut@@ Anna Benet-Pagès @@aut@@ Florentine Scharf @@aut@@ Ellen Heitzer @@aut@@ Ulrich Mansmann @@aut@@ Christopher Haberl @@aut@@ Maike de Wit @@aut@@ Holger Vogelsang @@aut@@ Markus Rentsch @@aut@@ Elke Holinski-Feder @@aut@@ Julia M. A. Pickl @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	568914813
id	DOAJ085117358
language_de	englisch
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Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. 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callnumber-first	R - Medicine
author	Ariane Hallermayr
spellingShingle	Ariane Hallermayr misc RC633-647.5 misc RC254-282 misc ctDNA misc Colorectal cancer misc Liquid biopsy misc Whole-genome sequencing misc Somatic copy number alterations misc cfDNA fragmentation misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
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topic_title	RC633-647.5 RC254-282 Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients ctDNA Colorectal cancer Liquid biopsy Whole-genome sequencing Somatic copy number alterations cfDNA fragmentation
topic	misc RC633-647.5 misc RC254-282 misc ctDNA misc Colorectal cancer misc Liquid biopsy misc Whole-genome sequencing misc Somatic copy number alterations misc cfDNA fragmentation misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC633-647.5 misc RC254-282 misc ctDNA misc Colorectal cancer misc Liquid biopsy misc Whole-genome sequencing misc Somatic copy number alterations misc cfDNA fragmentation misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC633-647.5 misc RC254-282 misc ctDNA misc Colorectal cancer misc Liquid biopsy misc Whole-genome sequencing misc Somatic copy number alterations misc cfDNA fragmentation misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
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title_full	Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
author_sort	Ariane Hallermayr
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author_browse	Ariane Hallermayr Tobias Wohlfrom Verena Steinke-Lange Anna Benet-Pagès Florentine Scharf Ellen Heitzer Ulrich Mansmann Christopher Haberl Maike de Wit Holger Vogelsang Markus Rentsch Elke Holinski-Feder Julia M. A. Pickl
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title_sort	somatic copy number alteration and fragmentation analysis in circulating tumor dna for cancer screening and treatment monitoring in colorectal cancer patients
callnumber	RC633-647.5
title_auth	Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
abstract	Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890.
abstractGer	Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890.
abstract_unstemmed	Abstract Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890.
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title_short	Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
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Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients

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