학술논문
Early Detection of Lung Cancer Using Small RNAs.
Document Type
Academic Journal
Author
Sikosek T; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Horos R; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Trudzinski F; Center for Interstitial and Rare Lung Diseases, Department of Pneumology and Critical Care Medicine, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.; Jehn J; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Frank M; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Rajakumar T; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Klotz LV; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.; Mercaldo N; Institute for Technology Assessment, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.; Kahraman M; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Heuvelman M; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Taha Y; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Gerwing J; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Skottke J; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Daniel-Moreno A; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Sanchez-Delgado M; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Bender S; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Rudolf C; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Hinkfoth F; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Tikk K; Hummingbird Diagnostics GmbH, Heidelberg, Germany.; Schenz J; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.; Weigand MA; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.; Feindt P; Klinik für Thoraxchirurgie, Clemenshospital Münster, Münster, Germany.; Schumann C; Klinik für Pneumologie, Thoraxonkologie, Schlaf- und Beatmungsmedizin, Klinikum Kempten und Klinik Immenstadt, Klinikverbund Allgäu, Kempten, Germany.; Christopoulos P; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.; Winter H; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.; Kreuter M; Mainz Center for Pulmonary Medicine, Departments of Pneumology, Mainz University Medical Center and of Pulmonary, Critical Care & Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany.; Schneider MA; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.; Muley T; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.; Walterspacher S; Lungenzentrum Bodensee, II. Medizinische Klinik, Klinikum Konstanz, Konstanz, Germany; Faculty of Health/School of Medicine, Witten/Herdecke University, Witten, Germany.; Schuler M; West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany.; Darwiche K; Klinik für Pneumologie, Universitätsmedizin Essen - Ruhrlandklinik, Essen, Germany.; Taube C; Klinik für Pneumologie, Universitätsmedizin Essen - Ruhrlandklinik, Essen, Germany.; Hegedus B; Department of Thoracic Surgery, University Medicine Essen, Ruhrlandklinik, Essen, Germany.; Rabe KF; LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research (DZL), Grosshansdorf, Germany; Department of Medicine, Christian Albrechts University of Kiel, Kiel, Germany.; Rieger-Christ K; Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts.; Jacobsen FL; Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.; Aigner C; Department of Thoracic Surgery, University Medicine Essen, Ruhrlandklinik, Essen, Germany.; Reck M; LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research (DZL), Grosshansdorf, Germany.; Bankier AA; Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.; Sharma A; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.; Steinkraus BR; Hummingbird Diagnostics GmbH, Heidelberg, Germany. Electronic address: bsteinkraus@hb-dx.com.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 101274235 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1556-1380 (Electronic) Linking ISSN: 15560864 NLM ISO Abbreviation: J Thorac Oncol Subsets: MEDLINE
Subject
Language
English
Abstract
Introduction: Lung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed tomography screening can reduce mortality; however, annual screening is limited by low adherence in the United States of America and still not broadly implemented in Europe. As a result, less than 10% of lung cancers are detected through existing programs. Thus, there is a great need for additional screening tests, such as a blood test, that could be deployed in the primary care setting.
Methods: We prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin.
Results: We generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84-0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71-0.76) for stage I to 0.90 (95% CI: 0.89-0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling.
Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer.
(Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Methods: We prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin.
Results: We generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84-0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71-0.76) for stage I to 0.90 (95% CI: 0.89-0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling.
Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer.
(Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)