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Article ; Online: Research Progress on Postoperative Minimal/Molecular Residual Disease Detection in Lung Cancer.

Wu, Manqi / Shen, Haifeng / Wang, Ziyang / Kanu, Nnennaya / Chen, Kezhong

Chronic diseases and translational medicine

2022 Volume 8, Issue 2, Page(s) 83–90

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA ...

Abstract	Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.
Language	English
Publishing date	2022-03-31
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2831148-6
ISSN	2589-0514 ; 2589-0514
ISSN (online)	2589-0514
ISSN	2589-0514
DOI	10.1002/cdt3.10
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Research Progress on Postoperative Minimal/Molecular Residual Disease Detection in Lung Cancer

Manqi Wu / Haifeng Shen / Ziyang Wang / Nnennaya Kanu / Kezhong Chen

Chronic Diseases and Translational Medicine, Vol 8, Iss 2, Pp 83-

2022 Volume 90

Abstract: Abstract Lung cancer is the leading cause of cancer‐related deaths worldwide. Approximately 10%–50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating ... ...

Abstract	Abstract Lung cancer is the leading cause of cancer‐related deaths worldwide. Approximately 10%–50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi‐analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.
Keywords	circulating tumor DNA ; liquid biopsy ; lung cancer ; minimal/molecular residual disease ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: An emerging regulatory network of NHEJ via DYNLL1-mediated 53BP1 redistribution.

Zalmas, Lykourgos-Panagiotis / Lu, Wei-Ting / Kanu, Nnennaya

Annals of translational medicine

2019 Volume 7, Issue Suppl 3, Page(s) S93

Language	English
Publishing date	2019-09-25
Publishing country	China
Document type	Editorial ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.04.39
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Article: APOBEC3 as a driver of genetic intratumor heterogeneity.

Venkatesan, Subramanian / Angelova, Mihaela / Bartkova, Jirina / Bakhoum, Samuel F / Bartek, Jiri / Kanu, Nnennaya / Swanton, Charles

Molecular & cellular oncology

2022 Volume 10, Issue 1, Page(s) 2014734

Abstract: Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor ...

Abstract	Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2021.2014734
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Article ; Online: A comparative analysis of the mutagenicity of platinum-containing chemotherapeutic agents reveals direct and indirect mutagenic mechanisms.

Szikriszt, Bernadett / Póti, Ádám / Németh, Eszter / Kanu, Nnennaya / Swanton, Charles / Szüts, Dávid

Mutagenesis

2021 Volume 36, Issue 1, Page(s) 75–86

Abstract: Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance and also induce secondary malignancies. We coupled whole genome sequencing ... ...

Abstract	Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and examine the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes, whereas the direct mutagenic effect appeared to correlate with the level of DNA damage caused as assessed through histone H2AX phosphorylation and single-cell agarose gel electrophoresis, the indirect mutagenic effects were equal. The different mutagenicity and DNA-damaging effect of equitoxic platinum drug treatments suggest that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Carboplatin/pharmacology ; Cells, Cultured ; Chickens ; Cisplatin/pharmacology ; DNA Damage ; Humans ; Lymphocytes/drug effects ; Lymphocytes/pathology ; Lymphoma/drug therapy ; Lymphoma/pathology ; Mutagenicity Tests ; Mutagens/adverse effects ; Oxaliplatin/pharmacology
Chemical Substances	Antineoplastic Agents ; Mutagens ; Oxaliplatin (04ZR38536J) ; Carboplatin (BG3F62OND5) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2021-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632903-2
ISSN	1464-3804 ; 0267-8357
ISSN (online)	1464-3804
ISSN	0267-8357
DOI	10.1093/mutage/geab005
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Article ; Online: Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer.

Chen, Kezhong / Yang, Fan / Shen, Haifeng / Wang, Chenyang / Li, Xi / Chervova, Olga / Wu, Shuailai / Qiu, Fujun / Peng, Di / Zhu, Xin / Chuai, Shannon / Beck, Stephan / Kanu, Nnennaya / Carbone, David / Zhang, Zhihong / Wang, Jun

Cancer cell

2023 Volume 41, Issue 10, Page(s) 1749–1762.e6

Abstract: We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection ...

Abstract	We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299 days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/surgery ; Carcinoma, Non-Small-Cell Lung/pathology ; Circulating Tumor DNA/analysis ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Lung Neoplasms/surgery ; Cell-Free Nucleic Acids ; DNA, Neoplasm ; Small Cell Lung Carcinoma ; Neoplasm, Residual/genetics ; Biomarkers, Tumor/genetics ; Neoplasm Recurrence, Local/genetics
Chemical Substances	Circulating Tumor DNA ; Cell-Free Nucleic Acids ; DNA, Neoplasm ; Biomarkers, Tumor
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.08.010
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Article ; Online: Individualized dynamic methylation-based analysis of cell-free DNA in postoperative monitoring of lung cancer.

Chen, Kezhong / Kang, Guannan / Zhang, Zhihong / Lizaso, Analyn / Beck, Stephan / Lyskjær, Iben / Chervova, Olga / Li, Bingsi / Shen, Haifeng / Wang, Chenyang / Li, Bing / Zhao, Heng / Li, Xi / Yang, Fan / Kanu, Nnennaya / Wang, Jun

BMC medicine

2023 Volume 21, Issue 1, Page(s) 255

Abstract: Background: The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the ... ...

Abstract	Background: The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients. Methods: Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36). Results: Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48-6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96-8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse. Conclusions: The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance. Trial registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 .
MeSH term(s)	Humans ; Cell-Free Nucleic Acids/genetics ; Circulating Tumor DNA/genetics ; Neoplasm Recurrence, Local/diagnosis ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Lung Neoplasms/surgery ; DNA Methylation/genetics ; Biomarkers, Tumor/genetics
Chemical Substances	Cell-Free Nucleic Acids ; Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2023-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131669-7
ISSN	1741-7015 ; 1741-7015
ISSN (online)	1741-7015
ISSN	1741-7015
DOI	10.1186/s12916-023-02954-z
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Article ; Online: Individualized dynamic methylation-based analysis of cell-free DNA in postoperative monitoring of lung cancer

Kezhong Chen / Guannan Kang / Zhihong Zhang / Analyn Lizaso / Stephan Beck / Iben Lyskjær / Olga Chervova / Bingsi Li / Haifeng Shen / Chenyang Wang / Bing Li / Heng Zhao / Xi Li / Fan Yang / Nnennaya Kanu / Jun Wang

BMC Medicine, Vol 21, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Background The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals ... ...

Abstract	Abstract Background The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients. Methods Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36). Results Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48–6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96–8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse. Conclusions The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance. Trial registration This study (MEDAL, MEthylation ...
Keywords	Lung cancer ; Postoperative surveillance ; Circulating tumor DNA (ctDNA) ; DNA methylation ; Minimal residual disease (MRD) ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quantifying the impact of immunotherapy on RNA dynamics in cancer.

Usaite, Ieva / Biswas, Dhruva / Dijkstra, Krijn / Watkins, Thomas Bk / Pich, Oriol / Puttick, Clare / Angelova, Mihaela / Thakkar, Krupa / Hiley, Crispin / Birkbak, Nicolai / Kok, Marleen / Zaccaria, Simone / Wu, Yin / Litchfield, Kevin / Swanton, Charles / Kanu, Nnennaya

Journal for immunotherapy of cancer

2023 Volume 11, Issue 11

Abstract: Background: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor ...

Abstract	Background: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. Methods: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. Results: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors Conclusions: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.
MeSH term(s)	Humans ; Female ; Melanoma/drug therapy ; Immunotherapy/adverse effects ; Combined Modality Therapy ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Tumor Microenvironment/genetics
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007870
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Article ; Online: Multi-omics integrated circulating cell-free DNA genomic signatures enhanced the diagnostic performance of early-stage lung cancer and postoperative minimal residual disease.

Li, Yun / Jiang, Guanchao / Wu, Wendy / Yang, Hao / Jin, Yichen / Wu, Manqi / Liu, Wenjie / Yang, Airong / Chervova, Olga / Zhang, Sujie / Zheng, Lu / Zhang, Xueying / Du, Fengxia / Kanu, Nnennaya / Wu, Lin / Yang, Fan / Wang, Jun / Chen, Kezhong

EBioMedicine

2023 Volume 91, Page(s) 104553

Abstract: Background: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform ...

Abstract	Background: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use. Methods: We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0). Findings: For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%. Interpretation: In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC. Funding: This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital.
MeSH term(s)	Humans ; Multiomics ; Neoplasm, Residual/diagnosis ; Neoplasm, Residual/genetics ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Lung Neoplasms/surgery ; Genomics/methods ; Cell-Free Nucleic Acids ; Biomarkers, Tumor
Chemical Substances	Cell-Free Nucleic Acids ; Biomarkers, Tumor
Language	English
Publishing date	2023-04-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104553
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