HIF-1alpha mRNA gene expression levels in improved diagnosis of early stages of prostate cancer.
OBJECTIVE
Several clinical studies have indicated that the rates of invasive growth and metastatic disease in cancer depend on the degree of hypoxia, which is mediated by hypoxia-inducible factor 1 alpha (HIF-1alpha). To determine its potential role as a marker for prostate cancer (CaP) diagnosis, HIF-1alpha mRNA levels were measured in blood samples of patients diagnosed with different stages of prostatic disease.


METHODS
HIF-1alpha mRNA levels were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and correlated with accurate clinicopathological data. Quantitative data were compared with serum prostate-specific antigen (PSA) measurements to determine variations in the accuracy of the CaP diagnosis.


RESULTS
HIF-1alpha mRNA levels were significantly upregulated in patients with localized CaP (LocCaP; n=63; p<0.0001), compared with patients with no evidence of malignancy (NEOM) and benign prostatic hyperplasia (BPH) (n=35 for both patient groups combined). Receiver operator characteristic (ROC) curve analysis demonstrated that HIF-1alpha specificity for the NEOM/BPH diagnosis was 88.6%. Sensitivity for LocCaP was 74.6% with an overall diagnostic efficiency of 79.6%. Specificity of the NEOM diagnosis at PSA levels of 4.0 ng ml(-1) was 28.6% and sensitivity of the LocCap diagnosis was 65.1%, demonstrating a reduced overall diagnostic efficiency, compared with that given by HIF-1alpha measurements, of 52.0%. Levels of HIF-1alpha in patients with metastatic CaP (MetCaP; n=27)) were similar to those in the NEOM/BPH group.


CONCLUSIONS
HIF-1alpha is upregulated early in CaP development with subsequent downregulation at later metastatic stages. This study demonstrates increased accuracy of early-stage disease diagnosis using HIF-1alpha qRT-PCR compared with serum PSA measurements. HIF-1alpha may therefore be a useful adjunct, together with other diagnostic markers used in relative qRT-PCR and current diagnostic techniques (including serum PSA and PSA velocity) to minimize unnecessary biopsies indicated by elevated serum PSA levels alone.
Pipinikas
Christodoulos P
CP
Division of Clinical Developmental Sciences, Medical Genetics, St George's University of London, Cranmer Terrace, London, UK. cpipinik@sgul.ac.uk
Carter
Nicholas D
ND
Corbishley
Catherine M
CM
Fenske
Christiane D
CD
D014408:Biomarkers, Tumor; D018450:Disease Progression; D055088:Early Detection of Cancer; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008297:Male; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000097:blood; D012334:RNA, Neoplasm / Q000097:blood*; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013997:Time Factors
D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017430:Prostate-Specific Antigen