Abstract 3440: Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors
Authors: McGrath Colleen B. , Shreves Alaina H. , Shanahan Megan R. , Guard Hannah E. , Nhliziyo Manelisi V. , Penney Kathryn L. , Lotan Tamara L. , Fiorentino Michelangelo , Stopsack Konrad H. , Mucci Lorelei A. 
Published: March 2024

Abstract
Background: The TMPRSS2:ERG gene fusion is the most common somatic alteration in primary prostate cancer and an early event in carcinogenesis. There are emerging data highlighting etiologic differences in prostate cancer by TMPRSS2:ERG status. This systematic review synthesized evidence from epidemiologic studies on prostate cancer risk factors for tumors with and without the TMPRSS2:ERG fusion.
Methods: A systematic literature search was performed in Ovid MEDLINE, EMBASE, and Web of Science without language restriction for studies published by September 27, 2022. Studies that assessed associations between epidemiologic and genetic factors and prostate cancer risk by tumor TMPRSS2:ERG (ERG) fusion status in human populations were included.
Results: Of 3,071 records identified, 20 publications comprising prospective cohort and case-control studies from five study populations (published 2009-2022) were included. Risk factors included germline genetic variants, circulating hormones, diet, lifestyle factors, and medications. The included studies suggested that taller height and higher total and free circulating testosterone levels tended to be associated with higher risk of ERG-positive, but not ERG-negative prostate cancer. CAG repeat length in the androgen receptor (AR) gene, related inversely to transcriptional activity, appeared to be associated with a lower risk of ERG-positive, but not ERG-negative prostate cancer. There was statistical evidence for etiologic differences for several germline single nucleotide polymorphisms (SNPs) by ERG status. Excess body weight, greater vigorous physical activity, greater lycopene intake, and calcium channel blocker use appeared to specifically be associated with a lower risk of ERG-positive tumors. Associations of other potential etiologic factors, including diabetes mellitus, baldness, aspirin use, circulating antioxidant levels, and sex hormones other than testosterone, with ERG-positive prostate cancer were null or inconclusive. Most associations had low precision, and the results were based on few distinct study populations, highlighting a need for replication.
Conclusions: Prostate cancer with the TMPRSS2:ERG fusion may be an etiologically distinct subtype impacted by certain modifiable and hormonally-acting risk factors that align with the established mechanistic role of this gene fusion in androgen, insulin, and growth factor pathways. The findings suggest a potentially distinct genetic predisposition to prostate cancer with or without the TMPRSS2:ERG fusion. More broadly, these findings suggest that considering molecular subtypes of prostate cancer, beyond TMPRSS2:ERG, may strengthen etiologic understanding of prostate cancer and evidence for prevention.
Citation Format: Colleen B. McGrath, Alaina H. Shreves, Megan R. Shanahan, Hannah E. Guard, Manelisi V. Nhliziyo, Kathryn L. Penney, Tamara L. Lotan, Michelangelo Fiorentino, Konrad H. Stopsack, Lorelei A. Mucci. Etiology of prostate cancer with the TMPRSS2:ERG fusion: A systematic review of risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3440.