Oncology Biomarkers
Urokinase-type Plasminogen Activator and Its Receptor
uPA and uPAR have been proposed as potential PCa diagnostic and prognostic biomarkers.121,122
uPA and uPAR serum levels were
observed to be significantly elevated in PCa patients compared with healthy men and significantly declined after radical prostatectomy.121 uPAR fragments were found to be significant univariate and multivariate predictors of PCa, and a multi-institutional study is ongoing to validate early results.122
The observation that the urokinase
plasminogen axis (uPA, uPAR and its inhibitors PAI-1 and PAI-2) seems to be related to features of biologically aggressive PCa and adverse clinical outcomes has been reported by several studies.121,123,124
Markers of Neuroendocrine Differentiation Chromogranin A (CgA) is a peptide overproduced by PCa tumours with neuroendocrine differentiation. PCa patients showed higher CgA serum concentrations, and when f/tPSA and CgA were combined the diagnostic sensitivity was enhanced (73% with 80% specificity).125 Increased CgA serum levels have been correlated with Gleason score, androgen-independent progression and poor prognosis.125,126 However, these findings were not confirmed by other groups.127 Serum progastrin-releasing peptide (ProGRP) is elevated in patients with advanced disease stage and have been associated with androgen-independent progression.128
In a multivariate model of
pre-treatment factors, serum ProGRP held an independent predictive value for progression-free survival.129
Table 2 summarises a selection of the most promising PCa biomarkers.130–149 Renal Cell Carcinoma Biomarkers
Most of the detected biomarkers for renal cell carcinoma (RCC) are directly related to the discovery of the Von Hippel-Lindau (VHL) gene defect and of the VHL protein, whose function is to regulate the transcription factor hypoxia inducible factor-1α (HIF-1α). HIF-1α induces the activation of many hypoxia-inducible genes such as vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CA9), which are discussed below. Many additional novel biomarkers are being discovered and validated, such as metalloprotease ADAM10, chemokine CXCL16, cell-surface glycoprotein B7-H1, neutrophil gelatinase-associated lipocalin (NGAL), survivin, glutathione-1, calveolin-1 and p53 protein.150
Vascular Endothelial Growth Factor
VEGF is a potent angiogenetic factor controlled by the VHL–HIF-1α pathway and overexpressed in clear cell RCC (ccRCC), but also in papillary and chromophobe RCCs.151–153
The overexpression of VEGF-A and Correlations have been
reported between VEGF expression in RCC tumour tissue with tumour size/stage and with prognosis.153
HIF-1α indicates a more aggressive subtype of ccRCC and portends poor prognosis in localised and metastatic RCC.154
expression increases the risk of death from RCC. A molecular signature of five markers, including epithelial VEGF-D, was found to be an independent prognostic indicator in ccRCC patients.155
Serum levels
of VEGF and NGAL were significant predictors of progression-free survival in patients with RCC treated with sunitinib.156
Carbonic Anhydrase IX CA9 is an HIF-1α-regulated transmembrane metalloenzyme that regulates intracellular and extracellular pH levels and that is strongly overexpressed in ccRCC.157
Protein levels of CA9, quantified by immunohistochemistry or by ELISA, seem to improve diagnostic 40 Low VEGF-D Testicular Cancer Biomarkers
Serum tumour markers have a key role in the management of patients with testicular cancer, contributing to diagnosis, staging, risk stratification, monitoring of response to treatment and early diagnosis of recurrence. Human chorionic gonadotropin (hCG and hCG-β), α-fetoprotein (AFP) and lactate dehydrogenase (LDH) are well established, universally accepted and commonly available serum markers with independent diagnostic and prognostic value for testicular tumours.164,165
Most cases of non-seminomatous germ cell
tumours are associated with elevated serum concentrations of one or more of these markers, while LDH and hCG are useful in seminomas. Other potentially useful experimental serum biomarkers have been evaluated, such as placental/germ-cell alkaline phosphatase (PLAP), pregnancy-specific β-1 glycoprotein (SP1), neuron-specific enolase (NSE) and lactate dehydrogenase isoenzyme 1 (LD-1).166–169
However, only small retrospective studies or small pilot studies are available for these molecules, and do not appear to provide additional clinical information.
Additional Investigational Approaches Combining multiple biomarkers represents an approach that is expected to improve the classification of cancer patients into separate prognostic categories. Promising results have been already reported using multiple urinary or tissue biomarkers.170–172
Multivariable tests, nomograms and artificial neural networks have been advocated for predicting diagnosis and prognosis in urological cancer patients.175–178
Another approach that has gained renewed interest is searching for DNA aberrant methylation of multiple genes. There is evidence that DNA methylation changes in urine and bodily fluids may be useful BCa biomarkers yielding additional diagnostic and prognostic information.173,174
Although exciting, these
approaches need to show clinically significant improvement in accuracy to gain extensive use in clinical practice. Combining phage display technology and protein microarrays in a new approach termed ‘cancer immunomics’, some authors were able to immunodetect circulating autoantibodies against PCa-associated antigens such as huntingtin-interaction protein 1, prostasomes and α-methyl-acyl-coenzymeA-racemase (AMACR). Wang et al.179 identified 186 autoantibody-binding peptides derived from CaP tissue and developed a 22-phage peptide microarray showing better accuracy than tPSA. Studies are under way to further validate this detection tool in a larger cohort.
In terms of sensitivity and specificity, promising results have been demonstrated in several studies using high-throughput genomic and proteomic profiling of biological fluids, tissues and cell lines, especially in the field of BCa and PCa biomarkers.180–188 However, many limitations due to pre-analytical, analytical and bioinformatic biases urge an accurate validation of this technique by independent laboratories.184,189,190
EUROPEAN UROLOGICAL REVIEW
accuracy for primary RCC as well as for metastatic RCC and may help differentiate between ccRCC and non-ccRCC.158–160
Interestingly, co-expression of CA9 and VEGF in The prognostic value
and a correlation with clinical outcomes and therapeutic response to immunotherapy in advanced-stage ccRCC have been recently demonstrated.157,161,162
ccRCC provided more accurate prognostic information than individual data. These promising data need further validation, taking in to account the conflicting results reported in a recent study.163
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84