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Page 2 of 12 Ossoliński et al. J Cancer Metastasis Treat 2019;5:1 I http://dx.doi.org/10.20517/2394-4722.2018.63

Keywords: Prostate cancer, biomarker, metabolomics, mass spectrometry

INTRODUCTION
Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and third leading cause of mortality
after lung and colorectal cancer among men in Western World. Overall, during lifetime, 1 in 6 men will
develop PCa and 1 in 33 will die from this disease. Moreover, at presentation 16% of patients will have locally
advanced or metastatic disease. Life expectancy depends mainly on the stage and varies between < 5 years
[1]
for metastatic disease to minimal risk of death at 15 years for organ-confined disease . Historically PCa was
diagnosed with digital rectal examination (DRE) followed by transperineal or digitally guided transrectal
biopsy, often in advanced stage. Introduction of prostate-specific antigen (PSA) testing has revolutionized
diagnosis of PCa and is shown to be the better predictor of cancer than DRE or transrectal ultrasound (TRUS).
Traditional PSA cutoff value for prostate biopsy is > 4 ng/mL and has only 33% specificity and 86% sensitivity
for detection of PCa. As a result patients with elevated PSA are overdiagnosed and overtreated. Decrease
in mortality from PCa observed in most Western countries is considered partially to be the result of PCa
screening with PSA. However, screening with PSA has become one of the most debated topics in urology
and is dominated by the conflicting results of 2 randomized control trials: The European Randomized Study
[2]
of Screening for Prostate Cancer (ERSPC) , which found a survival benefit due to screening with PSA (with
[3]
the greatest benefit within Goteborg arm of ERSPC trial ) while the United States Prostate, Lung, Colorectal,
[4]
and Ovarian Cancer Screening Trial did not. As ERSPC study shows, to save one patient from PCa specific
death, 1,055 men need to be screened and 37 patients need to be treated. Recent studies concluded that
screening is associated with increased diagnosis of PCa, no PCa-specific or overall survival benefit and
[5]
increased risk of overdiagnosis and overtreatment . Therefore new diagnostic tools (multiparametric MRI)
and biomarkers (PCA3, kallikreins and TMPRSS2-Erg fusion) are constantly being developed to increase
sensitivity and specificity of PCa testing. Recently a number of novel PCa biomarkers have been developed.
The most promising was developed by MDxHealth - SelectMDx. It is a genomic-based test that measures
the expression of two PCa-related mRNAs in urine: HOXC6 and DLX1 in conjunction with clinical risk
factors. It’s main advantage is the ability to diagnose patients with clinically significant cancer (Gleason score
≥ 7) which would be selected for prostate biopsy and to avoid identification of indolent PCa. SelectMDx
[6]
[7]
negative predictive value is 98% . According to Govers et al. application of SelectMDx in clinical practice
contributes to increased quality-adjusted life years while saving healthcare costs.
Biomarker research is based on analyzing differences in abundances of varied substances between cancerous
tissue or biofluid and their healthy counterpart. This comparative analysis approach identifies and classifies
the individual molecules. However, recently, a novel approach have been proposed and is called network-
based analysis. Instead of focusing on specific molecule, emphasis is placed on whole cellular pathway
and key molecules which are altered in the disease. Search for potential biomarkers has been conducted at
every molecular level: genome, transcriptome, proteome and metabolome. Genomic and transcriptomic
microarray, real time PCR and next gen. sequencing, proteomic and metabolomic mass spectrometry and
nuclear magnetic resonance spectroscopy in combination with advanced bioinformatics tools allowed
detailed insight into cancerogenesis. Metabolome, which is collection of all metabolites produced within cell
is an endpoint of the “omics cascade” (genomics, proteomics, metabolomics) pathway and in comparison
to genes and proteins which are subjected to epigenetic processes and post-translational modifications, is
[8]
the most accurate representation of phenotype . Recent advances in mass spectrometry enabled discovery
of numerous metabolites specific for lung, colorectal, ovarian, prostate, renal, breast and liver cancer [9-17] .
Metabolomic studies of PCa have led to the discovery of sarcosine as a potential marker of PCa. It has been
demonstrated that elevated level of serum sarcosine is associated with PCa [18,19] . However the role of sarcosine
as a potential PCa biomarker has been based on studies involving a small number of subjects and has been
[20]
questioned following publication of the studies of larger cohort. de Vogel et al. examined serum of 3000