Analysis of Urinary Midkine and Volatile Organic Compound (VOC) Levels Using a Breath Analyzer for Screening and Early Diagnosis of Lung Cancer
Downloads
Introduction: Lung cancer is the leading cause of cancer-related mortality worldwide. Midkine, a heparin-binding growth factor, promotes proliferation, angiogenesis, and metastasis. Volatile organic compounds (VOCs) reflect cellular and molecular changes, aiding in cancer diagnosis. This study explored urinary midkine and VOC profiles as biomarkers for lung cancer screening and early diagnosis.
Methods: A case-control, cross-sectional study was conducted on 20 controls (family members of lung cancer patients) and 20 lung cancer patients who had not received therapy. Volatile organic compounds breath analysis and urinary midkine measurements were performed. Volatile organic compounds, including total volatile organic compounds (TVOCs), ethanol (C2H5OH), formaldehyde (CH2O), toluene (C7H8), acetone (C3H6O), hexane (C6H14), and methane (CH4), were collected from exhaled breath using Tedlar bags and measured with a µβreath analyzer. Meanwhile, urinary midkine levels were determined using the Enzyme-Linked ImmunoSorbent Assay (ELISA) method. Statistical analyses included an independent t-test, Mann-Whitney U test, Spearman correlation, and diagnostic testing with receiver operating characteristic (ROC) analysis.
Results: Urinary midkine levels were higher in lung cancer patients than in controls (330.56±120.50 vs. 282.18±146.28 pg/mL), although not significant (p>0.05). The independent t-test revealed that ethanol levels were significantly elevated in lung cancer patients (p < 0.001), whereas methane levels were not (p > 0.50). Receiver operating characteristic analysis demonstrated sensitivity and specificity: urinary midkine (60%, 60%), ethanol (75%, 75%), and methane (45%, 45%).
Conclusion: Ethanol VOC appears to be a promising non-invasive biomarker for the early detection of lung cancer, whereas elevated urinary midkine levels did not demonstrate significant diagnostic value.
Thandra KC, Barsouk A, Saginala K, et al. Epidemiology of Lung Cancer. Contemp Oncol (Poznan, Poland) 2021; 25: 45–52. [PubMed]
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209–249. [PubMed]
Jia Z, Zhang H, Ong CN, et al. Detection of Lung Cancer: Concomitant Volatile Organic Compounds and Metabolomic Profiling of Six Cancer Cell Lines of Different Histological Origins. ACS Omega 2018; 3: 5131–5140. [PubMed]
Seijo LM, Peled N, Ajona D, et al. Biomarkers in Lung Cancer Screening: Achievements, Promises, and Challenges. J Thorac Oncol 2019; 14: 343–357. [PubMed]
Chen DT, Chan W, Thompson ZJ, et al. Utilization of Target Lesion Heterogeneity for Treatment Efficacy Assessment in Late Stage Lung Cancer. PLoS One 2021; 16: e0252041. [PubMed]
Hofman P. Liquid Biopsy for Early Detection of Lung Cancer. Curr Opin Oncol 2017; 29: 73–78. [PubMed]
Broza YY, Zhou X, Yuan M, et al. Disease Detection with Molecular Biomarkers: From Chemistry of Body Fluids to Nature-Inspired Chemical Sensors. Chem Rev 2019; 119: 11761–11817. [PubMed]
Gasparri R, Sedda G, Caminiti V, et al. Urinary Biomarkers for Early Diagnosis of Lung Cancer. J Clin Med; 10. Epub ahead of print April 2021. [PubMed]
Shin DH, Jo JY, Kim SH, et al. Midkine is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer. Cancers (Basel); 12. Epub ahead of print August 2020. [PubMed]
Buma AIG, Muller M, de Vries R, et al. eNose Analysis for Early Immunotherapy Response Monitoring in Non-Small Cell Lung Cancer. Lung Cancer 2021; 160: 36–43. [PubMed]
van Geffen WH, Lamote K, Costantini A, et al. The Electronic Nose: Emerging Biomarkers in Lung Cancer Diagnostics. Breathe (Sheffield, England) 2019; 15: e135–e141. [PubMed]
Li Z, Shu J, Yang B, et al. Emerging Non-Invasive Detection Methodologies for Lung Cancer. Oncol Lett 2020; 19: 3389–3399. [PubMed]
Riely GJ, Wood DE, Ettinger DS, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024; 22: 249–274. [PubMed]
Jusuf A, Wibawanto A, Icksan AG, et al. Kanker Paru. Jakarta, https://id.scribd.com/document/624214713/PDPI-Kanker-Paru-2018 (2018).
Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol 2022; 17: 362–387. [PubMed]
Corrales L, Rosell R, Cardona AF, et al. Lung Cancer in Never Smokers: The Role of Different Risk Factors other than Tobacco Smoking. Crit Rev Oncol Hematol 2020; 148: 102895. [PubMed]
LoPiccolo J, Gusev A, Christiani DC, et al. Lung Cancer in Patients Who Have Never Smoked - An Emerging Disease. Nat Rev Clin Oncol 2024; 21: 121–146. [PubMed]
Liu L, Teng J, Zhang L, et al. The Combination of the Tumor Markers Suggests the Histological Diagnosis of Lung Cancer. Biomed Res Int 2017; 2017: 2013989. [PubMed]
Alexandre D, Teixeira B, Rico A, et al. Molecular Beacon for Detection miRNA-21 as a Biomarker of Lung Cancer. Int J Mol Sci; 23. Epub ahead of print March 2022. [PubMed]
Association AL. State of Lung Cancer: 2022 Report. Chicago, https://www.lung.org/getmedia/647c433b-4cbc-4be6-9312-2fa9a449d489/solc-2022-print-report (2022).
Yang D, Liu Y, Bai C, et al. Epidemiology of Lung Cancer and Lung Cancer Screening Programs in China and the United States. Cancer Lett 2020; 468: 82–87. [PubMed]
Serasanambati M, Broza YY, Haick H. Volatile Compounds are Involved in Cellular Crosstalk and Upregulation. Adv Biosyst 2019; 3: e1900131. [PubMed]
Janfaza S, Khorsand B, Nikkhah M, et al. Digging Deeper into Volatile Organic Compounds associated with Cancer. Biol Methods Protoc 2019; 4: bpz014. [PubMed]
Oguma T, Nagaoka T, Kurahashi M, et al. Clinical Contributions of Exhaled Volatile Organic Compounds in the Diagnosis of Lung Cancer. PLoS One 2017; 12: e0174802. [PubMed]
Gashimova E, Temerdashev A, Porkhanov V, et al. Investigation of Different Approaches for Exhaled Breath and Tumor Tissue Analyses to Identify Lung Cancer Biomarkers. Heliyon 2020; 6: e04224. [PubMed]
Dananjaya A, Setyawan UA, Djajalaksana S, et al. Change in Exhaled Volatile Organic Compounds (VOC) Profile and Interleukin-17 Serum in Lung Cancer Patient. J Respirologi Indones 2023; 43: 9–14. [Journal]
Listiandoko RDW, Setyawan UA, Tri Wahju Astuti, et al. Volatile Organic Compounds (VOCs) and Interleukin-23 Levels in Lung Cancer: A Future Biomarker. J Respirasi 2023; 9: 80–86. [Journal]
Cai YQ, Lv Y, Mo ZC, et al. Multiple Pathophysiological Roles of Midkine in Human Disease. Cytokine 2020; 135: 155242. [PubMed]
Filippou PS, Karagiannis GS, Constantinidou A. Midkine (MDK) Growth Factor: A Key Player in Cancer Progression and a Promising Therapeutic Target. Oncogene 2020; 39: 2040–2054. [PubMed]
Xia X, Lu JJ, Zhang SS, et al. Midkine is a Serum and Urinary Biomarker for the Detection and Prognosis of Non-Small Cell Lung Cancer. Oncotarget 2016; 7: 87462–87472. [PubMed]
Hakim M, Broza YY, Barash O, et al. Volatile Organic Compounds of Lung Cancer and Possible Biochemical Pathways. Chem Rev 2012; 112: 5949–5966. [PubMed]
Schmidt F, Kohlbrenner D, Malesevic S, et al. Mapping the Landscape of Lung Cancer Breath Analysis: A Scoping Review (ELCABA). Lung Cancer 2023; 175: 131–140. [PubMed]
Copyright (c) 2025 Saidah Mafisah, Ungky Agus Setyawan, Rezki Tantular, Deden Permana, Susanthy Djajalaksana, Arinto Yudi Ponco Wardoyo, Aditya Sri Listyoko
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
1. The journal allows the author to hold the copyright of the article without restrictions.
2. The journal allows the author(s) to retain publishing rights without restrictions.
3. The legal formal aspect of journal publication accessibility refers to Creative Commons Attribution Share-Alike (CC BY-SA).
4. The Creative Commons Attribution Share-Alike (CC BY-SA) license allows re-distribution and re-use of a licensed work on the conditions that the creator is appropriately credited and that any derivative work is made available under "the same, similar or a compatible license”. Other than the conditions mentioned above, the editorial board is not responsible for copyright violation.
JR (