Identification of cancer biomarkers to allow early diagnosis is an urgent need for many types of tumors, whose prognosis strongly depends on the stage of the disease. Canine olfactory testing for detecting cancer is an emerging field of investigation. As an alternative, here we propose to use GC-Olfactometry (GC/O), which enables the speeding up of targeted biomarker identification and analysis. A pilot study was conducted in order to determine odor-active compounds in urine that discriminate patients with gastrointestinal cancers from control samples (healthy people).
Headspace solid phase microextraction (HS-SPME)-GC/MS and GC-olfactometry (GC/O) analysis were performed on urine samples obtained from gastrointestinal cancer patients and healthy controls.
In total, 91 key odor-active compounds were found in the urine samples. Although no odor-active biomarkers present were found in cancer carrier’s urine, significant differences were discovered in the odor activities of 11 compounds in the urine of healthy and diseased people. Seven of above mentioned compounds were identified: thiophene, 2-methoxythiophene, dimethyl disulphide, 3-methyl-2-pentanone, 4-(or 5-)methyl-3-hexanone, 4-ethyl guaiacol and phenylacetic acid. The other four compounds remained unknown.
GC/O has a big potential to identify compounds not detectable using untargeted GC/MS approach. This paves the way for further research aimed at improving and validating the performance of this technique so that the identified cancer-associated compounds may be introduced as biomarkers in clinical practice to support early cancer diagnosis.
The authors thank for the kind contribution of the spouses Mrs. Di Paola and Mr. Grimaldi ad memoriam of her beloved mother for the scientific research through Fondazione Italiana Biologi (FIB) (Grant/Award Number: “GAS16”).
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: The study was supported by a grant from the Italian Ministry of Health through Division of Gastroenterology (RC1403GA41 and RC1503GA40 to VP) IRCCS “Casa Sollievo della Sofferenza” Hospital and by the “5×1000” voluntary contributions. This research was supported also by European Regional Development Fund to Competence Center of Food and Fermentation Technologies (EU48667) and Institutional Research Funding to Tallinn University of Technology (IUT 19-27) of the Estonian Ministry of Education and Research and Industrie Alimentari Tamma s.r.l. (RV16GASTAMMA).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. Anderson BW, Ahlquist DA. Molecular detection of gastrointestinal neoplasia: Innovations in early detection and screening. Gastroenterol Clin North Am 2016;45:529–42.10.1016/j.gtc.2016.04.009Search in Google Scholar PubMed
2. 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:E359–86.10.1002/ijc.29210Search in Google Scholar PubMed
4. Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al. The global burden of cancer 2013. JAMA Oncol 2015;1:505–27.10.1001/jamaoncol.2015.0735Search in Google Scholar PubMed PubMed Central
5. Jin Z, Jiang W, Wang L. Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). Oncol Lett 2015;9:1502–8.10.3892/ol.2015.2959Search in Google Scholar PubMed PubMed Central
6. D’Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, et al. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget 2015;6:18545–57.10.18632/oncotarget.4186Search in Google Scholar PubMed PubMed Central
7. Vaccaro V, Sperduti I, Vari S, Bria E, Melisi D, Garufi C, et al. Metastatic pancreatic cancer: Is there a light at the end of the tunnel? World J Gastroenterol 2015;21:4788–801.10.3748/wjg.v21.i16.4788Search in Google Scholar PubMed PubMed Central
8. Tavano F, Fontana A, Pellegrini F, Burbaci FP, Rappa F, Cappello F, et al. Modeling interactions between Human Equilibrative Nucleoside Transporter-1 and other factors involved in the response to gemcitabine treatment to predict clinical outcomes in pancreatic ductal adenocarcinoma patients. J Transl Med 2014;12:248.10.1186/s12967-014-0248-4Search in Google Scholar PubMed PubMed Central
10. Probert CS, Ahmed I, Khalid T, Johnson E, Smith S, Ratcliffe N. Volatile organic compounds as diagnostic biomarkers in gastrointestinal and liver diseases. J Gastrointestin Liver Dis 2009;18:337–43.Search in Google Scholar
11. Sarosiek I, Schicho R, Blandon P, Bashashati M. Urinary metabolites as noninvasive biomarkers of gastrointestinal diseases: A clinical review. World J Gastrointest Oncol 2016;8:459–65.10.4251/wjgo.v8.i5.459Search in Google Scholar PubMed PubMed Central
13. Cornu JN, Cancel-Tassin G, Ondet V, Girardet C, Cussenot O. Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis. Eur Urol 2011;59:197–201.10.1016/j.eururo.2010.10.006Search in Google Scholar PubMed
14. Taverna G, Tidu L, Grizzi F, Torri V, Mandressi A, Sardella P, et al. Olfactory system of highly trained dogs detects prostate cancer in urine samples. J Urol 2015;193:1382–7.10.1016/j.juro.2014.09.099Search in Google Scholar PubMed
15. de Boer NK, de Meij TG, Oort FA, Ben Larbi I, Mulder CJ, van Bodegraven AA, et al. The scent of colorectal cancer: detection by volatile organic compound analysis. Clin Gastroenterol Hepatol 2014;12:1085–9.10.1016/j.cgh.2014.05.005Search in Google Scholar PubMed
16. Lesniak A, Walczak M, Jezierski T, Sacharczuk M, Gawkowski M, Jaszczak K. Canine olfactory receptor gene polymorphism and its relation to odor detection performance by sniffer dogs. J Hered 2008;99:518–27.10.1093/jhered/esn057Search in Google Scholar PubMed
17. Arasaradnam RP, Covington JA, Harmston C, Nwokolo CU. Review article: next generation diagnostic modalities in gastroenterology–gas phase volatile compound biomarker detection. Aliment Pharmacol Ther 2014;39:780–9.10.1111/apt.12657Search in Google Scholar PubMed
18. Brattoli M, Cisternino E, Dambruoso PR, de Gennaro G, Giungato P, Mazzone A, et al. Gas chromatography analysis with olfactometric detection (GC-O) as a useful methodology for chemical characterization of odorous compounds. Sensors (Basel) 2013;13:16759–800.10.3390/s131216759Search in Google Scholar PubMed PubMed Central
20. Kusano M, Mendez E, Furton KG. Comparison of the volatile organic compounds from different biological specimens for profiling potential. J Forensic Sci 2013;58:29–39.10.1111/j.1556-4029.2012.02215.xSearch in Google Scholar PubMed
21. Mazzone PJ, Wang XF, Lim S, Choi H, Jett J, Vachani A, et al. Accuracy of volatile urine biomarkers for the detection and characterization of lung cancer. BMC Cancer 2015;15:1001.10.1186/s12885-015-1996-0Search in Google Scholar PubMed PubMed Central
22. Huang J, Kumar S, Abbassi-Ghadi N, Spaněl P, Smith D, Hanna GB. Selected ion flow tube mass spectrometry analysis of volatile metabolites in urine headspace for the profiling of gastro-esophageal cancer. Anal Chem 2013;85:3409–16.10.1021/ac4000656Search in Google Scholar
23. Hanai Y, Shimono K, Matsumura K, Vachani A, Albelda S, Yamazaki K, et al. Urinary volatile compounds as biomarkers for lung cancer. Biosci Biotechnol Biochem 2012;76:679–84.10.1271/bbb.110760Search in Google Scholar
24. Khalid T, Aggio R, White P, De Lacy Costello B, Persad R, Al-Kateb H, et al. Urinary volatile organic compounds for the detection of prostate cancer. PLoS One 2015;10:e0143283.10.1371/journal.pone.0143283Search in Google Scholar
25. Navaneethan U, Parsi MA, Lourdusamy D, Grove D, Sanaka MR, Hammel JP, et al. Volatile organic compounds in urine for noninvasive diagnosis of malignant biliary strictures: A Pilot Study. Dig Dis Sci 2015;60:2150–7.10.1007/s10620-015-3596-xSearch in Google Scholar
26. Wang D, Wang C, Pi X, Guo L, Wang Y, Li M, et al. Urinary volatile organic compounds as potential biomarkers for renal cell carcinoma. Biomed Rep 2016;5:68–72.10.3892/br.2016.686Search in Google Scholar
27. Arasaradnam RP, McFarlane MJ, Ryan-Fisher C, Westenbrink E, Hodges P, Thomas MG, et al. Detection of colorectal cancer (CRC) by urinary volatile organic compound analysis. PLoS One 2014;9:e108750.10.1371/journal.pone.0108750Search in Google Scholar
28. Silva CL, Passos M, Camara JS. Investigation of urinary volatile organic metabolites as potential cancer biomarkers by solid-phase microextraction in combination with gas chromatography-mass spectrometry. Br J Cancer 2011;105:1894–4.10.1038/bjc.2011.437Search in Google Scholar
30. Pickel D, Manucy GP, Walker DB, Hall SB, Walker JC. Evidence for canine olfactory detection of melanoma. Applied Animal Behaviour Science 2004;89:107–16.10.1016/j.applanim.2004.04.008Search in Google Scholar
32. Williams M, Johnston JM. Training and maintaining the performance of dogs (Canis familiaris) on an increasing number of odor discriminations in a controlled setting. Appl Anim Behav Sci 2002;78:55–65.10.1016/S0168-1591(02)00081-3Search in Google Scholar
34. Craven BA, Paterson EG, Settles GS. The fluid dynamics of canine olfaction: unique nasal airflow patterns as an explanation of macrosmia. J Royal Soc Interface 2010;7:933–43.10.1098/rsif.2009.0490Search in Google Scholar PubMed PubMed Central
35. Di Gangi IM, Mazza T, Fontana A, Copetti M, Fusilli C, Ippolito A, et al. Metabolomic profile in pancreatic cancer patients: a consensus-based approach to identify highly discriminating metabolites. Oncotarget 2016;7:5815–29.10.18632/oncotarget.6808Search in Google Scholar PubMed PubMed Central
36. Pavai S, Yap SF. The clinical significance of elevated levels of serum CA 19-9. Med J Malaysia 2003;58:667–72.Search in Google Scholar
37. Fontana A, Copetti M, Di Gangi IM, Mazza T, Tavano F, Gioffreda D, et al. Development of a metabolites risk score for one-year mortality risk prediction in pancreatic adenocarcinoma patients. Oncotarget 2016;7:8968–78.10.18632/oncotarget.7108Search in Google Scholar PubMed PubMed Central
39. Urayama S, Zou W, Brooks K, Tolstikov V. Comprehensive mass spectrometry based metabolic profiling of blood plasma reveals potent discriminatory classifiers of pancreatic cancer. Rapid Commun Mass Spectrom 2010;24:613–20.10.1002/rcm.4420Search in Google Scholar PubMed
40. Wang S, Chen X, Tang M. Quantitative assessment of the diagnostic role of MUC1 in pancreatic ductal adenocarcinoma. Tumour Biol 2014;35:9101–9.10.1007/s13277-014-2186-4Search in Google Scholar PubMed
41. Brand RE, Nolen BM, Zeh HJ, Allen PJ, Eloubeidi MA, Goldberg M, et al. Serum biomarker panels for the detection of pancreatic cancer. Clin Cancer Res 2011;17:805–16.10.1158/1078-0432.CCR-10-0248Search in Google Scholar PubMed PubMed Central
42. Jezierski T, Walczak M, Ligor T, Rudnicka J, Buszewski B. Study of the art: canine olfaction used for cancer detection on the basis of breath odour. Perspectives and limitations. J Breath Res 2015;9:027001.10.1088/1752-7155/9/2/027001Search in Google Scholar PubMed
44. Wagenstaller M, Buettner A. Quantitative determination of common urinary odorants and their glucuronide conjugates in human urine. Metabolites 2013;3:637–57.10.3390/metabo3030637Search in Google Scholar PubMed PubMed Central
45. Quignon P, Kirkness E, Cadieu E, Touleimat N, Guyon R, Renier C, et al. Comparison of the canine and human olfactory receptor gene repertoires. Genome Biol 2003;4:R80.10.1186/gb-2003-4-12-r80Search in Google Scholar PubMed PubMed Central
46. Barh D, Carpi A, Verma M, Gunduz M. Cancer biomarkers: Minimal and noninvasive early diagnosis and prognosis. Boca Raton, Florida, USA: Taylor and Francis, CRC Press, 2014.10.1201/b16389Search in Google Scholar
47. Kwak J, Gallagher M, Ozdener MH, Wysocki CJ, Goldsmith BR, Isamah A, et al. Volatile biomarkers from human melanoma cells. J Chromatogr B Analyt Technol Biomed Life Sci 2013;931:90–6.10.1016/j.jchromb.2013.05.007Search in Google Scholar PubMed
48. Silva CL, Passos M, Camara JS. Solid phase microextraction, mass spectrometry and metabolomic approaches for detection of potential urinary cancer biomarkers–a powerful strategy for breast cancer diagnosis. Talanta 2012;89:360–8.10.1016/j.talanta.2011.12.041Search in Google Scholar PubMed
49. Garner CE, Smith S, de Lacy Costello B, White P, Spencer R, Probert CS, et al. Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease. Faseb J 2007;21:1675–88.10.1096/fj.06-6927comSearch in Google Scholar PubMed
50. Kakuta S, Nishiumi S, Yoshida M, Fukusaki E, Bamba T. Profiling of volatile compounds in APC(Min/+) mice blood by dynamic headspace extraction and gas chromatography/mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2015;1003:35–40.10.1016/j.jchromb.2015.09.002Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston