Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors

The most common somatic alteration in primary prostate cancer is the TMPRSS2:ERG gene fusion, which may be caused or promoted by distinct etiologic factors. The objective of this systematic review was to assess epidemiologic evidence on etiologic factors for prostate cancer by tumor TMPRSS2:ERG fusion status in human populations. Of 3071 publications identified, 19 cohort or case-control studies from six distinct study populations were included in this systematic review. Etiologic factors included germline genetic variants, circulating hormones, and dietary and lifestyle factors. Taller height, higher total and free testosterone levels, and fewer trinucleotide repeats in AR were possibly associated with higher risk of TMPRSS2:ERG-positive prostate cancer. Excess body weight, greater vigorous physical activity, higher lycopene intake, and the use of calcium channel blockers were associated with lower risk of TMPRSS2:ERG-positive prostate cancer. Diabetes and family history of prostate cancer were associated with both TMPRSS2:ERG-positive and TMPRSS2:ERG-negative prostate cancer. Prostate cancer germline variants had suggestive differential associations with TMPRSS2:ERG-positive or TMPRSS2:ERG-negative prostate cancer. However, results were based on few distinct study populations and generally had low precision, underscoring the need for replication. In conclusion, prostate cancer with TMPRSS2:ERG fusion is an etiologically distinct subtype that may be, in part, preventable by addressing modifiable and hormonally acting etiologic factors that align with the established mechanistic role of TMPRSS2:ERG in androgen, insulin, antioxidant, and growth factor pathways.