Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG

Abstract

Background: TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.

Methods: The study included 1243 participants in the prospective Physicians' Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P interaction = .001).

Conclusions: These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.

Figure 1.

Hazard ratios (HR) for lethal prostate cancer by cross-classified categories of body mass index (BMI) and ERG tumor status. Hazard ratios were calculated using Cox proportional hazards regression models and are represented by black squares. Men with ERG-negative tumors and BMI of 18.5 to <25kg/m² is the reference category. Column heights represent the 95% confidence intervals.

Figure 2.

Distributions of tumor protein expression intensity by ERG tumor status. A) Insulin receptor (IR). B) IGF-1 receptor (IGF-1R). C) Adiponectin receptor 2 (AdipoR2). D) Fatty acid synthase (FASN).