Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective
Objective: Sputum is a source of exfoliated respiratory epithelial cells transformed early in lung carcinogenesis. Malignant cells are hypomethylated and contain less genomic 5-methylcytosine (5mC). Validating a test that recognizes and quantifies aberrantly hypomethylated cells in sputum, we assess...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | JTCVS Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666273622004156 |
| _version_ | 1797860363331436544 |
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| author | Harmik J. Soukiasian, MD Alexander Leung, MD Taryne Imai, MD Shika Bose, MD Sungjin Kim, MS Zab Mosenifar, MD Nirdesh K. Gupta, PhD Jian Tajbakhsh, PhD |
| author_facet | Harmik J. Soukiasian, MD Alexander Leung, MD Taryne Imai, MD Shika Bose, MD Sungjin Kim, MS Zab Mosenifar, MD Nirdesh K. Gupta, PhD Jian Tajbakhsh, PhD |
| author_sort | Harmik J. Soukiasian, MD |
| collection | DOAJ |
| description | Objective: Sputum is a source of exfoliated respiratory epithelial cells transformed early in lung carcinogenesis. Malignant cells are hypomethylated and contain less genomic 5-methylcytosine (5mC). Validating a test that recognizes and quantifies aberrantly hypomethylated cells in sputum, we assessed its potential as a screening tool for detecting early-stage non–small cell lung cancer. Methods: Cells extracted from sputum were immunofluorescence labeled with an anti-5-methylcytosine antibody and counterstained with 4′,6-diamidino-2-phenylindole (DAPI) delineating global nuclear DNA (gDNA). Via confocal scanning and 3-dimensional image analysis, fluorescence 5mC and DAPI signals were measured in segmented cell nuclei, and a 5mC/DAPI co-distribution map was generated for each imaged cell. Cells were classified as hypomethylated based on 5mC load and 5mC/DAPI co-distribution. The proportion of hypomethylated epithelial cells in the sputum determines whether a patient has lung cancer. Results: A total of 88 subjects were enrolled: 12 healthy subjects; 34 high-risk subjects with benign chronic lung disorders (10 with chronic obstructive pulmonary disease, 24 with idiopathic pulmonary fibrosis), and 43 subjects with non–small cell lung cancer (27 with stage I-II and 16 with stage III-IV). The test identified early-stage non–small cell lung cancer and distinguished it from the high-risk group with 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 41.2% (95% confidence interval, 24.6-59.3) specificity applying only 5mC, 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 26.5% (95% confidence interval, 12.9-44.4) specificity using solely 5mC/DAPI index, and 100% (95% confidence interval, 98.7-100) sensitivity and 26.1% (95% confidence interval, 26.2-27.8) specificity with the combined parameters. Conclusions: We tested and validated a novel, noninvasive, highly sensitive screening test for non–small cell lung cancer. With the use of sputum, our test may impact lung cancer screening, evaluation of pulmonary nodules, and cancer surveillance algorithms. |
| first_indexed | 2024-04-09T21:44:39Z |
| format | Article |
| id | doaj.art-8fc245e695b14c91a911f0d1118d76f2 |
| institution | Directory Open Access Journal |
| issn | 2666-2736 |
| language | English |
| last_indexed | 2024-04-09T21:44:39Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTCVS Open |
| spelling | doaj.art-8fc245e695b14c91a911f0d1118d76f22023-03-25T05:15:31ZengElsevierJTCVS Open2666-27362023-03-0113389410Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspectiveHarmik J. Soukiasian, MD0Alexander Leung, MD1Taryne Imai, MD2Shika Bose, MD3Sungjin Kim, MS4Zab Mosenifar, MD5Nirdesh K. Gupta, PhD6Jian Tajbakhsh, PhD7Division of Thoracic Surgery, Cedars-Sinai, Los Angeles, CalifDivision of Thoracic Surgery, Cedars-Sinai, Los Angeles, CalifDivision of Thoracic Surgery, Cedars-Sinai, Los Angeles, CalifDepartment of Pathology, Cedars-Sinai, Los Angeles, CalifSamuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CalifDepartment of Medicine, Cedars-Sinai, Los Angeles, Calif3rd Street Diagnostics, Cedars-Sinai, Los Angeles, CalifSamuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, Calif; 3rd Street Diagnostics, Cedars-Sinai, Los Angeles, Calif; Address for reprints: Jian Tajbakhsh, PhD, 3rd St Diagnostics, Faculty, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.Objective: Sputum is a source of exfoliated respiratory epithelial cells transformed early in lung carcinogenesis. Malignant cells are hypomethylated and contain less genomic 5-methylcytosine (5mC). Validating a test that recognizes and quantifies aberrantly hypomethylated cells in sputum, we assessed its potential as a screening tool for detecting early-stage non–small cell lung cancer. Methods: Cells extracted from sputum were immunofluorescence labeled with an anti-5-methylcytosine antibody and counterstained with 4′,6-diamidino-2-phenylindole (DAPI) delineating global nuclear DNA (gDNA). Via confocal scanning and 3-dimensional image analysis, fluorescence 5mC and DAPI signals were measured in segmented cell nuclei, and a 5mC/DAPI co-distribution map was generated for each imaged cell. Cells were classified as hypomethylated based on 5mC load and 5mC/DAPI co-distribution. The proportion of hypomethylated epithelial cells in the sputum determines whether a patient has lung cancer. Results: A total of 88 subjects were enrolled: 12 healthy subjects; 34 high-risk subjects with benign chronic lung disorders (10 with chronic obstructive pulmonary disease, 24 with idiopathic pulmonary fibrosis), and 43 subjects with non–small cell lung cancer (27 with stage I-II and 16 with stage III-IV). The test identified early-stage non–small cell lung cancer and distinguished it from the high-risk group with 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 41.2% (95% confidence interval, 24.6-59.3) specificity applying only 5mC, 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 26.5% (95% confidence interval, 12.9-44.4) specificity using solely 5mC/DAPI index, and 100% (95% confidence interval, 98.7-100) sensitivity and 26.1% (95% confidence interval, 26.2-27.8) specificity with the combined parameters. Conclusions: We tested and validated a novel, noninvasive, highly sensitive screening test for non–small cell lung cancer. With the use of sputum, our test may impact lung cancer screening, evaluation of pulmonary nodules, and cancer surveillance algorithms.http://www.sciencedirect.com/science/article/pii/S2666273622004156DNA methylationnoninvasive testnon–small cell lung cancerscreeningsputum |
| spellingShingle | Harmik J. Soukiasian, MD Alexander Leung, MD Taryne Imai, MD Shika Bose, MD Sungjin Kim, MS Zab Mosenifar, MD Nirdesh K. Gupta, PhD Jian Tajbakhsh, PhD Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective JTCVS Open DNA methylation noninvasive test non–small cell lung cancer screening sputum |
| title | Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective |
| title_full | Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective |
| title_fullStr | Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective |
| title_full_unstemmed | Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective |
| title_short | Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cellsCentral MessagePerspective |
| title_sort | highly sensitive noninvasive early lung cancer detection using dna methylation topology in sputum derived epithelial cellscentral messageperspective |
| topic | DNA methylation noninvasive test non–small cell lung cancer screening sputum |
| url | http://www.sciencedirect.com/science/article/pii/S2666273622004156 |
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