Gas chromatography and mass spectrometry for prostate cancer diagnosis: perspectives and achievements

Introduction. Prostate cancer (PCa) is one of the most common malignancies among men, making the search for new methods of its early detection highly relevant. Existing diagnostic approaches, such as the determination of prostate-specific antigen (PSA) levels, have limited specificity and sensitivity, highlighting the need for more accurate and non-invasive diagnostic methods.

Objecive. To analyze recent studies focused on the use of gas chromatography coupled with mass spectrometry (GC–MS) for the detection of urinary volatile organic compounds (VOCs) as potential PCa biomarkers, as well as to evaluate the prospects for the implementation of this method in clinical practice.

Materials & Methods. The review includes an analysis of scientific publications available in the PubMed, Medscape, and eLibrary databases for the period from 2019 to 2024. The focus was placed on studies devoted to urine metabolomic profiling using GC–MS and investigations of metabolic pathway alterations in prostate cancer cells.

Results. The results of the reviewed studies demonstrate that GC–MS enables the identification of specific VOCs associated with tumor transformation of prostate cells. This method shows high diagnostic accuracy, exceeding traditional approaches such as PSA testing. Metabolites such as sarcosine, acylcarnitine, and arachidonoilamine have been identified as demonstrating high sensitivity and specificity in the diagnosis of PCa. Alterations in carbohydrate and lipid metabolism, as well as activation of the pentose phosphate pathway, were also observed in PCa cells.

Conclusion. The use of GC-MS for VOC analysis in urine is a promising method for diagnosing prostate cancer, offering high accuracy and non-invasiveness. However, implementing this method into clinical practice requires addressing several technical and methodological issues, including standardizing protocols and reducing equipment costs. Further development of metabolomics and refinement of analytical methods could significantly improve early PCa diagnosis, positively impacting prognosis and quality of life for patients.

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. DOI: 10.3322/caac.21660

2. Hoffman A, Half EE. Update on Screening for Urological Malignancies. Rambam Maimonides Med J. 2017;8(4):e0041. DOI: 10.5041/RMMJ.10318

3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. Erratum in: CA Cancer J Clin. 2021;71(4):359. DOI: 10.3322/caac.21654

4. Adhyam M, Gupta AK. A Review on the Clinical Utility of PSA in Cancer Prostate. Indian J Surg Oncol. 2012;3(2):120-129. DOI: 10.1007/s13193-012-0142-6

5. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, Fanti S, Fossati N, Gandaglia G, Gillessen S, Grivas N, Grummet J, Henry AM, van der Kwast TH, Lam TB, Lardas M, Liew M, Mason MD, Moris L, Oprea-Lager DE, van der Poel HG, Rouvière O, Schoots IG, Tilki D, Wiegel T, Willemse PM, Cornford P. EAUEANM- ESTRO-ESUR-SIOG Guidelines on Prostate Cancer-2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2021;79(2):243-262. DOI: 10.1016/j.eururo.2020.09.042

6. Bax C, Taverna G, Eusebio L, Sironi S, Grizzi F, Guazzoni G, Capelli L. Innovative Diagnostic Methods for Early Prostate Cancer Detection through Urine Analysis: A Review. Cancers (Basel). 2018;10(4):123. DOI: 10.3390/cancers10040123

7. Pepe P, Panella P, Savoca F, Cacciola A, D’Arrigo L, Dibenedetto G, Pennisi M, Aragona F. Prevalence and clinical significance of prostate cancer among 12,682 men with normal digital rectal examination, low PSA levels (< or =4 ng/ml) and percent free PSA cutoff values of 15 and 20%. Urol Int. 2007;78(4):308-312. DOI: 10.1159/000100833

8. Becerra MF, Atluri VS, Bhattu AS, Punnen S. Serum and urine biomarkers for detecting clinically significant prostate cancer. Urol Oncol. 2021;39(10):686-690. DOI: 10.1016/j.urolonc.2020.02.018

9. Filella X, Fernández-Galan E, Fernández Bonifacio R, Foj L. Emerging biomarkers in the diagnosis of prostate cancer. Pharmgenomics Pers Med. 2018;11:83-94. DOI: 10.2147/PGPM.S136026

10. Pinu FR, Goldansaz SA, Jaine J. Translational Metabolomics: Current Challenges and Future Opportunities. Metabolites. 2019;9(6):108. DOI: 10.3390/metabo9060108

11. Liu Q, Fan Y, Zeng S, Zhao Y, Yu L, Zhao L, Gao J, Zhang X, Zhang Y. Volatile organic compounds for early detection of prostate cancer from urine. Heliyon. 2023;9(6):e16686. DOI: 10.1016/j.heliyon.2023.e16686

12. Jordan KW, Nordenstam J, Lauwers GY, Rothenberger DA, Alavi K, Garwood M, Cheng LL. Metabolomic characterization of human rectal adenocarcinoma with intact tissue magnetic resonance spectroscopy. Dis Colon Rectum. 2009;52(3):520-525. DOI: 10.1007/DCR.0b013e31819c9a2c

13. Rigau M, Olivan M, Garcia M, Sequeiros T, Montes M, Colás E, Llauradó M, Planas J, Torres Id, Morote J, Cooper C, Reventós J, Clark J, Doll A. The present and future of prostate cancer urine biomarkers. Int J Mol Sci. 2013;14(6):12620-12649. DOI: 10.3390/ijms140612620

14. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2(2):127-129. DOI: 10.1038/s42255-020-0172-2

15. Fujita K, Nonomura N. Urinary biomarkers of prostate cancer. Int J Urol. 2018;25(9):770-779. DOI: 10.1111/iju.13734

16. Tsouko E, Khan AS, White MA, Han JJ, Shi Y, Merchant FA, Sharpe MA, Xin L, Frigo DE. Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth. Oncogenesis. 2014;3(5):e103. DOI: 10.1038/oncsis.2014.18

17. Pujana-Vaquerizo M, Bozal-Basterra L, Carracedo A. Metabolic adaptations in prostate cancer. Br J Cancer. 2024;131(8):1250-1262. DOI: 10.1038/s41416-024-02762-z

18. Lucarelli G, Rutigliano M, Galleggiante V, Giglio A, Palazzo S, Ferro M, Simone C, Bettocchi C, Battaglia M, Ditonno P. Metabolomic profiling for the identification of novel diagnostic markers in prostate cancer. Expert Rev Mol Diagn. 2015;15(9):1211-1224. DOI: 10.1586/14737159.2015.1069711

19. Pértega-Gomes N, Baltazar F. Lactate transporters in the context of prostate cancer metabolism: what do we know? Int J Mol Sci. 2014;15(10):18333-18348. DOI: 10.3390/ijms151018333

20. Baenke F, Peck B, Miess H, Schulze A. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech. 2013;6(6):1353-1363. DOI: 10.1242/dmm.011338

21. Broadfield LA, Pane AA, Talebi A, Swinnen JV, Fendt SM. Lipid metabolism in cancer: New perspectives and emerging mechanisms. Dev Cell. 2021;56(10):1363-1393. DOI: 10.1016/j.devcel.2021.04.013

22. Bedair M, Sumner LW. Current and emerging mass-spectrometry technologies for metabolomics. Trends in Analytical Chemistry. 2008;27(3):238–250. DOI: 10.1016/j.trac.2008.01.006

23. Gladilovich V.D., Podolskaya E.P. Possibilities of gas chromatographymass spectrometry (review). Nauchnoe priborostroenie. 2010;20(4):36- 49. (In Russian).

24. Morrow-Jr. KJ. Mass Spec Central to Metabolomics. Genetic Engineering & Biotechnology News. 2010;30(7):1–3.

25. Jansen JJ, Hoefsloot HCJ, Greef J van der, Timmerman ME, Westerhuis JA, Smilde AK. ASCA: analysis of multivariate data obtained from an experimental design. Journal of Chemometrics. 2005;19:376–386. DOI: 10.1002/cem.952

26. Nicholson JK, Lindon JC. Systems biology: Metabonomics. Nature. 2008;455(7216):1054-1056. DOI: 10.1038/4551054a

27. Gates SC, Sweeley CC. Quantitative metabolic profiling based on gas chromatography. Clin Chem. 1978;24(10):1663-1673. PMID: 359193

28. Novotny MV, Soini HA, Mechref Y. Biochemical individuality reflected in chromatographic, electrophoretic and mass-spectrometric profiles. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;866(1-2):26-47. DOI: 10.1016/j.jchromb.2007.10.007

29. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly MA, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau DD, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan GE, Macinnis GD, Weljie AM, Dowlatabadi R, Bamforth F, Clive D, Greiner R, Li L, Marrie T, Sykes BD, Vogel HJ, Querengesser L. HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007;35(Database issue):D521-6. DOI: 10.1093/nar/gkl923

30. Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B, Hau DD, Psychogios N, Dong E, Bouatra S, Mandal R, Sinelnikov I, Xia J, Jia L, Cruz JA, Lim E, Sobsey CA, Shrivastava S, Huang P, Liu P, Fang L, Peng J, Fradette R, Cheng D, Tzur D, Clements M, Lewis A, De Souza A, Zuniga A, Dawe M, Xiong Y, Clive D, Greiner R, Nazyrova A, Shaykhutdinov R, Li L, Vogel HJ, Forsythe I. HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 2009;37(Database issue):D603-10. DOI: 10.1093/nar/gkn810

31. Gómez-Cebrián N, García-Flores M, Rubio-Briones J, López-Guerrero JA, Pineda-Lucena A, Puchades-Carrasco L. Targeted Metabolomics Analyses Reveal Specific Metabolic Alterations in High-Grade Prostate Cancer Patients. J Proteome Res. 2020;19(10):4082-4092. DOI: 10.1021/acs.jproteome.0c00493

32. Cerrato A, Bedia C, Capriotti AL, Cavaliere C, Gentile V, Maggi M, Montone CM, Piovesana S, Sciarra A, Tauler R, Laganà A. Untargeted metabolomics of prostate cancer zwitterionic and positively charged compounds in urine. Anal Chim Acta. 2021;1158:338381. DOI: 10.1016/j.aca.2021.338381

33. Vignoli A, Ghini V, Meoni G, Licari C, Takis PG, Tenori L, Turano P, Luchinat C. High-Throughput Metabolomics by 1D NMR. Angew Chem Int Ed Engl. 2019;58(4):968-994. DOI: 10.1002/anie.201804736

34. Buszewska-Forajta M, Raczak-Gutknecht J, Struck-Lewicka W, Nizioł M, Artymowicz M, Markuszewski M, Kordalewska M, Matuszewski M, Markuszewski MJ. Untargeted Metabolomics Study of Three Matrices: Seminal Fluid, Urine, and Serum to Search the Potential Indicators of Prostate Cancer. Front Mol Biosci. 2022;9:849966. DOI: 10.3389/fmolb.2022.849966

35. Lokhov PG, Dashtiev MI, Bondartsov LV, Lisitsa AV, Moshkovskii SA, Archakov AI. Metabolic fingerprinting of blood plasma from patients with prostate cancer. Biochem. Moscow Suppl. 2010;(Ser. B 4):37-41. DOI: 10.1134/S1990750810010051

36. Lokhov PG, Balashova EE, Trifonova OP, Maslov DL, Archakov AI. Desiat’ let rossiĭskoĭ metabolomike: istoriia razvitiia i osnovnye rezul’taty [Ten years of the Russian metabolomics: history of development and achievements]. Biomed Khim. 2020;66(4):279-293. (In Russian). DOI: 10.18097/PBMC20206604279

37. Lokhov PG, Dashtiev MI, Moshkovskii SA, Archakov AI. Metabolite profiling of blood plasma of patients with prostate cancer. Metabolomics. 2010;(6):156–163. DOI: 10.1007/s11306-009-0187-x

38. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910-914. Erratum in: Nature. 2013;499(7459):504. DOI: 10.1038/nature07762

39. Cernei N, Heger Z, Gumulec J, Zitka O, Masarik M, Babula P, Eckschlager T, Stiborova M, Kizek R, Adam V. Sarcosine as a potential prostate cancer biomarker--a review. Int J Mol Sci. 2013;14(7):13893-13908. DOI: 10.3390/ijms140713893

40. Yousefi M, Qujeq D, Shafi H, Tilaki K H. Serum and Urine Levels of Sarcosine in Benign Prostatic Hyperplasia and Newly Diagnosed Prostate Cancer Patients. J Kermanshah Univ Med Sci. 2020;24(1):e97000. DOI: 10.5812/jkums.97000.

41. Khalid T, Aggio R, White P, De Lacy Costello B, Persad R, Al-Kateb H, Jones P, Probert CS, Ratcliffe N. Urinary Volatile Organic Compounds for the Detection of Prostate Cancer. PLoS One. 2015;10(11):e0143283. DOI: 10.1371/journal.pone.0143283

42. Gao Q, Su X, Annabi MH, Schreiter BR, Prince T, Ackerman A, Morgas S, Mata V, Williams H, Lee WY. Application of Urinary Volatile Organic Compounds (VOCs) for the Diagnosis of Prostate Cancer. Clin Genitourin Cancer. 2019;17(3):183-190. DOI: 10.1016/j.clgc.2019.02.003

43. Ahmed Laskar A, Younus H. Aldehyde toxicity and metabolism: the role of aldehyde dehydrogenases in detoxification, drug resistance and carcinogenesis. Drug Metab Rev. 2019;51(1):42-64. DOI: 10.1080/03602532.2018.1555587

44. Lima AR, Pinto J, Barros-Silva D, Jerónimo C, Henrique R, Bastos ML, Carvalho M, Guedes Pinho P. New findings on urinary prostate cancer metabolome through combined GC-MS and 1H NMR analytical platforms. Metabolomics. 2020;16(6):70. DOI: 10.1007/s11306-020-01691-1

45. Yu C, Niu L, Li L, Li T, Duan L, He Z, Zhao Y, Zou L, Wu X, Luo C. Identification of the metabolic signatures of prostate cancer by mass spectrometry- based plasma and urine metabolomics analysis. Prostate. 2021;81(16):1320-1328. DOI: 10.1002/pros.24229

46. Wang W, He Z, Kong Y, Liu Z, Gong L. GC-MS-based metabolomics reveals new biomarkers to assist the differentiation of prostate cancer and benign prostatic hyperplasia. Clin Chim Acta. 2021;519:10-17. DOI: 10.1016/j.cca.2021.03.021

47. Riccio G, Berenguer CV, Perestrelo R, Pereira F, Berenguer P, Ornelas CP, Sousa AC, Vital JA, Pinto MDC, Pereira JAM, Greco V, Câmara JS. Differences in the Volatilomic Urinary Biosignature of Prostate Cancer Patients as a Feasibility Study for the Detection of Potential Biomarkers. Curr Oncol. 2023;30(5):4904-4921. DOI: 10.3390/curroncol30050370