Abstract A91: Obesity and the TMPRSS2:ERG translocation in prostate cancer

The recently identified TMPRSS2:ERG translocation is an early and common somatic event in prostate cancer pathogenesis involving the TMPRSS2 promotor, which is androgen regulated, and ERG, a member of the ETS family of transcriptional factors. Regulation of TMPRSS2 by androgens is intriguing and suggests both a potential mechanism whereby a man’s hormonal milieu could drive the progression of prostate tumor cells and also a mechanism by which androgen deprivation therapy may work. We explored the relationship of obesity, with its known relation with lower circulating testosterone and higher estradiol, on prostate cancer risk according to TMPRSS2:ERG fusion status.

The study was nested among 29,067 men in the prospective Physicians’ Health Study (PHS) during 1982 to 2008. Information on obesity was collected through structured questionnaires at baseline and follow-up, and included total obesity (weight and body mass index, BMI) and central obesity (waist circumference) measures. We characterized the TMPRSS2:ERG fusion by fluorescence in situ hybridization on archival tumor tissue from 305 men diagnosed with incident prostate cancer during 25 years of follow-up. We applied logistic regression models to compare the association of obesity on relative risk of fusion positive and fusion negative prostate cancer.

Almost half the men in PHS were overweight (BMI 25-26.9 kg/m²) or very overweight/obese (BMI 27 kg/m² or greater) at the start of follow-up. Prevalence of the TMPRSS2:ERG translocation among the men with prostate cancer was 40.0%, in line with other studies. The association of obesity on prostate cancer risk differed in relation to the translocation. Men with a higher BMI at baseline had a reduced risk of developing fusion positive prostate cancer (7% lower risk per increase in BMI, p for trend ~ 0.0021). Compared to healthy weight men, those who were very overweight/obese had a 60% lower risk of fusion positive prostate cancer (RR=0.43, 95% CI 0.22-0.83). Moreover, men with a larger waist circumference were at lower risk of developing fusion positive cancer (p for trend ~0.0017). In contrast, there was no association between total or central adiposity measures at baseline and risk of fusion-negative prostate cancer.

Obesity appears to reduce the risk of prostate tumors that carry the TMPRSS2:ERG fusion, but is unrelated to risk of prostate cancers that occur via fusion-independent mechanisms. These preliminary data provide insight into the link between the hormonal milieu and the heterogeneity of prostate cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A91.