Urine sampling: A non-invasive way to improve diagnostic efficiency for ovarian cancer

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Urine sampling: A non-invasive way to improve diagnostic efficiency for ovarian cancer
6/05/2022

 

Ovarian cancer - A silent killer

Ovarian cancer (OvCa) is the seventh most common malignancy among women worldwide. More than 70% of diagnosed women present the disease at an advanced stage, making the cancer type the most lethal of all gynecological malignancies. Patients with advanced stage OvCa have a 20 to 40% five-year survival rate, compared to 90% in women with stage I (1), meaning the cancer is only limited to the ovaries, (2) highlighting the importance of early detection and treatment.

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However, due to lack of clear symptoms and efficient diagnostic tools, OvCa is difficult to detect at an early stage (3). Current diagnostic methods are invasive, consisting of a pelvic examination, transvaginal ultrasonography (TVUS), and blood tests to detect cancer antigen 125 (CA125), often preventing women from testing early and easily. In many cases, surgery is also required to make a positive diagnosis (4).

To improve detection and reduce the high death rate among OvCa patients, better and more non-invasive diagnostic tests are needed (5).

Urine as a promising sample type in cancer research

Compared to blood, urine is a non-invasive sample type and available in large quantities. Urine is an excellent liquid biopsy that could provide a more convenient and accurate way for diagnosing malignant tumors (1). In general, urine is more stable compared to serum in relation to pre-analytical handling procedures (5).

The potential of urine as a source of biomarkers has been investigated in various cancer types, including for OvCa (6). Biomarker testing in urine can provide a non-invasive method for the early detection of ovarian carcinoma. It can also allow frequent testing of women who belong to high-risk groups (7) as well as, follow up on the treatment, and provide longitudinal follow-up of patients (8).

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Proteomics - HE4 is a potential urinary biomarker for ovarian cancer

The study of proteins, especially urinary proteins has shown to be promising for non-invasive OvCa detection. The urinary proteome is a direct product of renal filtration, resulting in a less complex matrix, consisting of soluble, low molecular weight peptides compared to the serum. Consequently, it contains fewer factors known to interfere with biomarker assays, which can be advantageous in a proteomic analysis (1).

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Among a wide spectrum of proteomic biomarkers, human epididymis protein 4 (HE4), approved by the FDA in 2008 for monitoring patients with OvCa for disease recurrence, has shown to be the most promising. Unlike CA125, which is elevated at different levels depending on the cancer stage, HE4 is not overexpressed in normal ovarian tissue, benign ovarian disease, or tumors with low malignant potential. The results of a meta-analysis indicated that 76% of OvCa patients had high HE4 levels, while 92% of the non OvCa patients had low HE4 levels (9).

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Further, urine obtained from 295 patients with pelvic masses scheduled for surgery, the urinary concentration of 17 biomarkers showed significant differences between patient with OvCa and benign tumors. HE4, vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were present in higher concentrations in OvCa patients, with HE4 demonstrating the highest differences in all OvCa samples (1). Additionally, patients with tumors of low malignant potential were more often positive for HE4 in urine compared to serum (10).

However, there is yet some debate in the field – a review concluded that currently the urinary biomarkers may be insufficient for the effective detection of OvCa at stage I and II, but may be superior when used alongside other non-urinary biomarkers and TVUS (4). Consequently, additional studies must be performed to verify the potential and accuracy of proteins as a diagnostic biomarker for OvCa (9).

 

Metabolomics - An emerging field of study for ovarian cancer

Metabolomics, the study of chemical processes in the human body involving metabolites, has shown to provide insights into various disease pathologies (11). A variety of metabolomics signatures specific to OvCa have been identified. Lipids and amino acid pathways have shown to be the most promising circulating signatures of OvCa (2). The clinical applications of metabolomics, however, is still limited. To effectively use these metabolomics signatures for OvCa screening and monitoring, further studies on large homogeneous populations including validation are needed (3).

Recently a meta-analysis study has been published on metabolomics studies for the discovery of OvCa diagnostic biomarkers (12). Initial data show for OvCa metabolites belonging to lipids and AA pathways are important, although the clinical application appears to be limited and additional studies are required (13).

Transcriptomics – miRNAs are exciting biomarkers for ovarian cancer

Transcriptomics, the study of RNA transcripts, including post- transcriptional regulation of gene expression microRNAs (miRNAs), are an emerging source of biomarkers for many cancer types (3).

Urine seems to be a potential source of biomarker in several diseases, including solid tumors. Several, miRNAs are misregulated in OvCa. A study identified significant upregulation of miR-30a-5p in urine samples of OvCa patients when compared to healthy controls (14). Also, miRNAs from the miR-200 family were underexpressed in the normal human ovarian surface epithelium and overexpressed in OvCa. miRNAs are key in the downstream of oncogenic pathways involved in cancer progression, this provides the rationale as also a promising target for therapy (12).

Conclusion

While further evaluation and validation are necessary, initial evidence is promising for urine based OvCa detection. Urine testing in conjunction with other diagnostic tools could help screen for ovarian cancer more quickly and precisely, allowing treatment to begin sooner.

However, to use urine for clinical applications, the pre-analytical variation, including collection, transport and storage must be kept to a minimum. Collection through a standard urine cup can be awkward, messy and inconvenient for the user.

To overcome these challenges, Novosanis developed Colli-Pee®, a urine collection device that allows for standardized and volumetric collection of urine. The device architecture also enables immediate mixing with preservative, improving sample stability. Further, to allow multi-omic testing and address low biomarker concentrations, we are also recently launched a Colli-Pee® Large Volumes variant, about 40 mL, which is available neat or with our new preservative UAS developed for usage in oncology research.

References:

  1. Lee SW, Lee HY, Bang HJ, Song HJ, Kong SW, Kim YM. An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy. Int J Mol Sci. 2019 Oct 5;20(19):4938. doi: 10.3390/ijms20194938. PMID: 31590408; PMCID: PMC6801627.
  2. https://www.cancerresearchuk.org/about-cancer/ovarian-cancer/stages-grades
  3. Saorin A, Di Gregorio E, Miolo G, Steffan A, Corona G. Emerging Role of Metabolomics in Ovarian Cancer Diagnosis. Metabolites. 2020 Oct 19;10(10):419. doi: 10.3390/metabo10100419. PMID: 33086611; PMCID: PMC7603269.
  4. Grayson K, Gregory E, Khan G, Guinn BA. Urine Biomarkers for the Early Detection of Ovarian Cancer - Are We There Yet? Biomark Cancer. 2019 Feb 26;11:1179299X19830977. doi: 10.1177/1179299X19830977. PMID: 30833816; PMCID: PMC6393943.
  5. Petri AL, Simonsen AH, Yip TT, Hogdall E, Fung ET, Lundvall L, Hogdall C. Three new potential ovarian cancer biomarkers detected in human urine with equalizer bead technology. Acta Obstet Gynecol Scand. 2009;88(1):18-26. doi: 10.1080/00016340802443830. PMID: 19023702.
  6. Bonifácio VDB. Ovarian Cancer Biomarkers: Moving Forward in Early Detection. Adv Exp Med Biol. 2020;1219:355-363. doi: 10.1007/978-3-030-34025-4_18. PMID: 32130708
  7. Lee SW, Lee HY, Bang HJ, Song HJ, Kong SW, Kim YM. An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy. Int J Mol Sci. 2019 Oct 5;20(19):4938. doi: 10.3390/ijms20194938. PMID: 31590408; PMCID: PMC6801627.
  8. Hellstrom I, Heagerty PJ, Swisher EM, Liu P, Jaffar J, Agnew K, Hellstrom KE. Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms. Cancer Lett. 2010 Oct 1;296(1):43-8. doi: 10.1016/j.canlet.2010.03.013. Epub 2010 Apr 8. PMID: 20381233; PMCID: PMC3156592.
  9. Jia MM, Deng J, Cheng XL, Yan Z, Li QC, Xing YY, Fan DM, Tian XY. Diagnostic accuracy of urine HE4 in patients with ovarian cancer: a meta-analysis. Oncotarget. 2017 Feb 7;8(6):9660-9671. doi: 10.18632/oncotarget.14173. PMID: 28039447; PMCID: PMC5354761.
  10. Liao JB, Yip YY, Swisher EM, Agnew K, Hellstrom KE, Hellstrom I. Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms: Clinical correlates. Gynecol Oncol. 2015 Jun;137(3):430-5. doi: 10.1016/j.ygyno.2015.03.044. Epub 2015 Apr 9. PMID: 25866324; PMCID: PMC4447602.
  11. Chen Z, Kim J. Urinary proteomics and metabolomics studies to monitor bladder health and urological diseases. BMC Urol. 2016 Mar 22;16:11. doi: 10.1186/s12894-016-0129-7. PMID: 27000794; PMCID: PMC4802825.
  12. Gasparri ML, Casorelli A, Bardhi E, Besharat AR, Savone D, Ruscito I, Farooqi AA, Papadia A, Mueller MD, Ferretti E, Benedetti Panici P. Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer. Tumour Biol. 2017 May;39(5):1010428317695525. doi: 10.1177/1010428317695525. PMID: 28459207.
  13. Saorin A, Di Gregorio E, Miolo G, Steffan A, Corona G. Emerging Role of Metabolomics in Ovarian Cancer Diagnosis. Metabolites. 2020 Oct 19;10(10):419. doi: 10.3390/metabo10100419. PMID: 33086611; PMCID: PMC7603269.
  14. Nakamura K, Sawada K, Yoshimura A, Kinose Y, Nakatsuka E, Kimura T. Clinical relevance of circulating cell-free microRNAs in ovarian cancer. Mol Cancer. 2016 Jun 24;15(1):48. doi: 10.1186/s12943-016-0536-0. PMID: 27343009; PMCID: PMC4921011.