We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism.
Recent advances in genomics and next-generation sequencing heralded the discovery of biomarkers such as the androgen receptor gene (<i>AR</i>) splice events, the <i>TMPRSS2:EGR</i> gene fusion, long noncoding RNA <i>MALAT-1</i> and <i>SCHLAP1</i> for PCa prognosis.
Comparison between human umbilical vein endothelial cell and prostate cancerTMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles.
The purpose of this study was to first investigate the expression of seven different PC-related RNAs that included serine 2 (TMPRSS2): erythroblastosis virus E26 oncogene homolog (ERG) gene (TMPRSS2-ERG, T2E) fusion, alpha-methylacyl-CoA racemase (AMACR), kallikrein related peptidase 3 (KLK3), androgen receptor (AR), prostate cancer specific antigen 3 (PCA3), and matrix metalloproteinases (MMP)-2 and 9.
We also assessed how these two markers correlated with the most common genetic alteration in prostate cancer: TMPRSS2 fusion to ERG (40-60% of carcinomas at the primary site), which places ERG expression under the control of the androgen-regulated TMPRSS2 gene, increasing expression.
Additionally, we revealed such genes for the <i>TMPRSS2-ERG</i> prostate cancer molecular subtype (<i>B4GALNT4</i>, <i>ASRGL1</i>, <i>MYBPC1</i>, <i>RGS11</i>, <i>SLC6A14</i>, <i>GALNT13</i>, and <i>ST6GALNAC1</i>).
With the advances in deep sequencing technology, a series of new PCa biomarkers have been recently proposed to improve the diagnostic value of PSA, such as prostate cancer antigen 3 (PCA3), TMPRSS2-ETS fusion gene, microRNA, and other regulatory non-coding RNAs.
Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States.
Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients.
Importantly, androgens exert a major role in PCa formation and progression and one of the hypothesized mechanism proposed has been linked to the chromosomal rearrangement of the androgen regulated gene TMPRSS2 with ERG.
TMPRSS2:ERG is the most frequent gene rearrangement identified in prostate cancer, but whether it is involved in prostate cancer bone metastases is largely unknown.
The TMPRSS2:ERG (T:E) fusion gene is generally believed to be mainly regulated by the activated androgen receptor (AR) signaling in androgen-dependent prostate cancer.
Higher body mass index (BMI) at baseline (per 5 kg/m<sup>2</sup> HR 0.75; 95% CI, 0.61-0.91; <i>P</i><sub>heterogeneity</sub> = 0.02) and updated BMI over time (per 5 kg/m<sup>2</sup> HR 0.86; 95% CI, 0.74-1.00; <i>P</i><sub>heterogeneity</sub> = 0.07) were associated with a reduced risk of ERG-positive disease only.<b>Conclusions:</b> Our results indicate that anthropometrics may be uniquely associated with <i>TMPRSS2:ERG</i>-positive prostate cancer; taller height may be associated with greater risk, whereas obesity may be associated with lower risk.<b>Impact:</b> Our study provides strong rationale for further investigations of other prostate cancer risk factors that may be distinctly associated with subtypes.
Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers.
The <i>TMPRSS2:ERG</i> fusion was expressed in 41% of samples, and the aggressive prostate cancer-associated long noncoding RNA <i>SChLAP1</i> was upregulated in 70%.
<i>TMPRSS2:ERG</i> status was assessed by IHC for presence of ERG on archival tumor specimens for 912 patients with prostate cancer, of whom 48% were ERG-positive.<b>Results:</b> In multivariable models, we found no association between regular use of aspirin and risk of <i>ERG</i>-positive prostate cancer (HR, 1.02; 95% confidence interval, 0.85-1.23), nor any association with duration or frequency of aspirin use.
Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 (TMPRSS2) and genes from the ETS transcription factor family, most commonly ERG and ETV1, result in alteration that responsible for oncogenic activity in prostate cancer (PC).
Correlative studies in human prostate cancers reveal a frequent association of the TMPRSS2/ERG (TE) fusion gene with loss of PTEN and studies in mouse models reveal that ERG expression and PTEN loss synergistically promote prostate cancer progression.