Abstract
Cervical cancer is a common cancer among women and has a high morbidity and mortality. The traditional clinical methods for cervical cancer screening are invasive and limited in terms of cost and time. There is an unmet clinical need for new methods to aid clinicians in the rapid screening and auxiliary diagnosis of cervical precancer. Recently, breath analysis has become an attractive approach for investigation of cancer biomarkers and shows great potential in cancer screening owing to its high sensitivity, quickness, and non-invasive nature. In this pilot study, breath analysis by proton transfer reaction mass spectrometry (PTR-MS) was utilized for online analysis of the exhaled breath of 13 cervical cancer patients and 34 female healthy volunteers. The Mann–Whitney U test and stepwise forward linear discriminant analysis were performed for data statistics. On the basis of the statistical analysis, four characteristic ions at m/z 76, 87, 93, and 121 were found for discriminating cervical cancer. The sensitivity and specificity were calculated to be 92.3% and 88.2%, respectively, using the stepwise discriminant analysis. The possible identities of characteristic ions were also discussed in detail. Although there are some uncertainties in the identification of these characteristic ions and more participants (including cervical cancer patients and healthy volunteers) are needed to further confirm the results, the results in this study demonstrate that the online breath test using PTR-MS is a promising approach for cervical cancer screening.
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Change history
25 September 2017
An erratum to this article has been published.
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.
Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA-Cancer J Clin. 2012;62(3):147–72.
Partridge EE, Abu-Rustum N, Giuliano A, Massad S, McClure J, Dwyer M, et al. Cervical cancer screening. J Natl Compr Cancer Netw. 2014;12(3):333–41.
Lyng FM, Traynor D, Ramos IRM, Bonnier F, Byrne HJ. Raman spectroscopy for screening and diagnosis of cervical cancer. Anal Bioanal Chem. 2015;407(27):8279–89.
Partridge EE, Abu-Rustum NR, Campos SM, Fahey PJ, Farmer M, Garcia RL, et al. Cervical cancer screening. J Natl Compr Cancer Netw. 2010;8(12):1358–86.
Huchko MJ, Sneden J, Sawaya G, Smith-McCune K, Maloba M, Abdulrahim N, et al. Accuracy of visual inspection with acetic acid to detect cervical cancer precursors among HIV-infected women in Kenya. Int J Cancer. 2014;136(2):392–8.
Verdoodt F, Jentschke M, Hillemanns P, Racey CS, Snijders PJF, Arbyn M. Reaching women who do not participate in the regular cervical cancer screening programme by offering self-sampling kits: a systematic review and meta-analysis of randomised trials. Eur J Cancer. 2015;51(16):2375–85.
Phillips M, Gleeson K, Hughes JMB, Greenberg J, Cataneo RN, Baker L, et al. Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study. Lancet. 1999;353(9168):1930–3.
Rieder J, Lirk P, Ebenbichler C, Gruber G, Prazeller P, Lindinger W, et al. Analysis of volatile organic compounds: possible applications in metabolic disorders and cancer screening. Wien Klin Wochenschr. 2001;113(5-6):181–5.
Nakhleh MK, Amal H, Jeries R, Broza YY, Aboud M, Gharra A, et al. Diagnosis and classification of 17 diseases from 1404 subjects via pattern analysis of exhaled molecules. ACS Nano. 2017;11(1):112–25.
Amal H, Shi DY, Ionescu R, Zhang W, Hua QL, Pan YY, et al. Assessment of ovarian cancer conditions from exhaled breath. Int J Cancer. 2015;136(6):614–22.
Nick A. Stop and smell the volatile organic compounds: a novel breath-based bioassay for detection of ovarian cancer. Gynecol Oncol. 2011;120(1):S54–5.
Kahn N, Lavie O, Paz M, Segev Y, Haick H. Dynamic nanoparticle-based flexible sensors: diagnosis of ovarian carcinoma from exhaled breath. Nano Lett. 2015;15(10):7023–8.
Berchtold C, Bosilkovska M, Daali Y, Walder B, Zenobi R. Real-time monitoring of exhaled drugs by mass spectrometry. Mass Spectrom Rev. 2014;33(5):394–413.
Sun XH, Shao K, Wang T. Detection of volatile organic compounds (VOCs) from exhaled breath as noninvasive methods for cancer diagnosis. Anal Bioanal Chem. 2016;408(11):2759–80.
Gordon SM, Szidon JP, Krotoszynski BK, Gibbons RD, Oneill HJ. Volatile organic-compounds in exhaled air from patients with lung-cancer. Clin Chem. 1985;31(8):1278–82.
Phillips M, Cataneo RN, Saunders C, Hope P, Schmitt P, Wai J. Volatile biomarkers in the breath of women with breast cancer. J Breath Res. 2010;4(2):8.
Smith D, Španěl P, Herbig J, Beauchamp J. Mass spectrometry for real-time quantitative breath analysis. J Breath Res. 2014;8(2):027101.
Millonig G, Praun S, Netzer M, Baumgartner C, Dornauer A, Mueller S, et al. Non-invasive diagnosis of liver diseases by breath analysis using an optimized ion-molecule reaction mass spectrometry approach: a pilot study. Biomarkers. 2010;15(4):297–306.
Soares LG, Jonski G, Tinoco EMB, Young A. Short-term effect of strontium- and zinc-containing toothpastes and mouthrinses on volatile sulphur compounds in morning breath: a randomized, double- blind, cross-over clinical study. Eur J Oral Sci. 2015;123(2):72–9.
Wang TS, Pysanenko A, Dryahina K, Spanel P, Smith D. Analysis of breath, exhaled via the mouth and nose, and the air in the oral cavity. J Breath Res. 2008;2(3):13.
Zou X, Zhou W, Lu Y, Shen C, Hu Z, Wang H, et al. Exhaled gases online measurements for esophageal cancer patients and healthy people by proton transfer reaction mass spectrometry. J Gastroen Hepatol. 2016;31(11):1837–43.
Shen CY, Li JQ, Wang HZ, Zhi ZH, Wang HM, Huang CQ, et al. Proton transfer reaction mass spectrometry for on-line detection of trace volatile organic compounds in breath. Chinese J Anal Chem. 2012;40(5):773–7.
Kumar S, Huang JZ, Abbassi-Ghadi N, Spanel P, Smith D, Hanna GB. Selected ion flow tube mass spectrometry analysis of exhaled breath for volatile organic compound profiling of esophago-gastric cancer. Anal Chem. 2013;85(12):6121–8.
Steinbacher BM, Dommen J, Ammann C, Spirig C, Neftel A, Prevot ASH. Performance characteristics of a protontransfer-reaction mass spectrometer (PTR-MS) derived from laboratory and field measurements. Int J Mass Spectrom. 2010;239(s 2–3):117–28.
Hansel A, Jordan A, Holzinger R, et al. Proton transfer reaction mass spectrometry: on-line trace gas analysis at the ppb level. Int J Mass Spectrom. 1995;150:609–19.
Maione C, Batista BL, Campiglia AD, Barbosa F, Barbosa RM. Classification of geographic origin of rice by data mining and inductively coupled plasma mass spectrometry. Comput Electron Agric. 2016;121:101–7.
Ulanowska A, Trawinska E, Sawrycki P, Buszewski B. Chemotherapy control by breath profile with application of SPME-GC/MS method. J Sep Sci. 2012;35(21):2908–13.
Broza YY, Kremer R, Tisch U, Gevorkyan A, Shiban A, Best LA, et al. A nanomaterial-based breath test for short-term follow-up after lung tumor resection. Nanomed-Nanotechnol Biol Med. 2013;9(1):15–21.
Endre ZH, Pickering JW, Storer MK, Hu WP, Moorhead KT, Allardyce R, et al. Breath ammonia and trimethylamine allow real-time monitoring of haemodialysis efficacy. Physiol Meas. 2011;32(1):115–30.
Miekisch W, Schubert JK, Noeldge-Schomburg GFE. Diagnostic potential of breath analysis - focus on volatile organic compounds. Clin Chim Acta. 2004;347(1-2):25–39.
Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Curr Drug Metab. 2005;6(3):227–40.
Cruden DL, Galask RP. Reduction of trimethylamine oxide to trimethylamine by Mobiluncus strains isolated from patients with bacterial vaginosis. Microb Ecol Health Dis. 2009;1(2):95–100.
Wolrath H, Stahlbom B, Hallen A, Forsum U. Trimethylamine and trimethylamine oxide levels in normal women and women with bacterial vaginosis reflect a local metabolism in vaginal secretion as compared to urine. Apmis. 2005;113(7-8):513–6.
Sardas S, Akyol D, Green RL, Mellon T, Gokmen O, Cholerton S. Trimethylamine N-oxidation in Turkish women with bacterial vaginosis. Pharmacogenetics. 1996;6(5):459–63.
Lazenby GB, Taylor PT, Badman BS, McHaki E, Korte JE, Soper DE, et al. An association between trichomonas vaginalis and high-risk human papillomavirus in rural Tanzanian women undergoing cervical cancer screening. Clin Ther. 2014;36(1):38–45.
de Lacy Costello B, Amann A, Al-Kateb H, Flynn C, Filipiak W, Khalid T, et al. A review of the volatiles from the healthy human body. J Breath Res. 2014;8(1):29.
Hakim M, Broza YY, Barash O, Peled N, Phillips M, Amann A, et al. Volatile organic compounds of lung cancer and possible biochemical pathways. Chem Rev. 2012;112(11):5949–66.
Kumar S, Huang JZ, Abbassi-Ghadi N, Mackenzie HA, Veselkov KA, Hoare JM, et al. Mass spectrometric analysis of exhaled breath for the identification of volatile organic compound biomarkers in esophageal and gastric adenocarcinoma. Ann Surg. 2015;262(6):981–90.
Brunner C, Szymczak W, Hollriegl V, Mortl S, Oelmez H, Bergner A, et al. Discrimination of cancerous and non-cancerous cell lines by headspace-analysis with PTR-MS. Anal Bioanal Chem. 2010;397(6):2315–24.
Filipiak W, Sponring A, Filipiak A, Ager C, Schubert J, Miekisch W, et al. TD-GC-MS analysis of volatile metabolites of human lung cancer and normal cells in vitro. Cancer Epidemiol Biomarkers Prev. 2010;19(1):182–95.
Ulanowska A, Kowalkowski T, Trawinska E, Buszewski B. The application of statistical methods using VOCs to identify patients with lung cancer. J Breath Res. 2011;5(4):11.
Ulmer H, Borena W, Rapp K, Klenk J, Strasak A, Diem G, et al. Serum triglyceride concentrations and cancer risk in a large cohort study in Austria. Br J Cancer. 2009;101(7):1202–6.
Peng G, Hakim M, Broza YY, Billan S, Abdah-Bortnyak R, Kuten A, et al. Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors. Br J Cancer. 2010;103(4):542–51.
Xu YW, Lee H, Hu YS, Huang JY, Kim S, Yun M. Detection and identification of breast cancer volatile organic compounds biomarkers using highly-sensitive single nanowire array on a chip. J Biomed Nanotechnol. 2013;9(7):1164–72.
Hanai Y, Shimono K, Oka H, Baba Y, Yamazaki K, Beauchamp GK. Analysis of volatile organic compounds released from human lung cancer cells and from the urine of tumor-bearing mice. Cancer Cell Int. 2012;12:12.
Tzeng TH, Kuo CY, Wang SY, Huang PK, Huang YM, Hsieh WC, et al. Portable micro gas chromatography system for lung cancer associated volatile organic compound detection. IEEE J Solid-State Circuit. 2016;51(1):259–72.
Acknowledgements
This research was funded by the National Natural Science Foundation of China (Nos. 81401483, 21477132, 21107112) and National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2015BAI01B04, 2013BAH14F01).