A central feature of this proposal is to directly assess VAT-associated inflammation independently of BMI via state-of-the-art Olink proteomic panel (384 inflammation-related proteins) that describe metabolic health (i.e., HOMA-IR, A1c, or lipoprotein insulin resistance score) with combinations of VAT (based on dual-energy X-ray absorptiometry) and BMI. This will allow blood-based measures of VAT-associated inflammation (termed “inflammotype” here) disentangled from BMI. In addition, because longitudinal patterns of adiposity over the life course may vary (e.g., obese consistently throughout life; later life weight gain in men leaner earlier in life), a single measure of BMI throughout life is unlikely to be adequate and methods require repeated life course measures, dealing with latency and potential opposing effects of adiposity at different life stages.
This study can be done cost-effectively based on newly assessed data as well as data already available from 4 cohorts: SCCS, HPFS, PHS and PLCO. Our specific aims are:
Aim 1: We will determine the role of VAT-specific inflammation in the risk of advanced PCa, stratified by age at diagnosis (<65y, ≥65y), BMI (<25, ≥25 kg/m2) and race (Black, White) ► We hypothesize that VAT-specific inflammation (“inflammotype”) is associated with higher risk of advanced PCa, especially in older men, men with relatively low BMI (subcutaneous adiposity), and in Black men. In secondary analyses, we will examine associations of inflammotype with free T and IGF1 in categories of age, BMI, and race, to test if chronic inflammation is the primary factor associated with age-related reductions in free T and IGF1.
Aim 2: We will examine prediagnostic levels of free T, IGF1 and inflammotype in relation to risk of advanced PCa molecular subtypes defined by TMPRSS2:ERG fusion and tumor-associated inflammation ► We hypothesize that higher free T and IGF1 are associated with higher risk of TMPRSS2:ERG positive PCa (in younger men); and that higher VAT-specific inflammation is associated with i) higher risk of TMPRSS2:ERG positive PCa (in older men) and ii) higher risk of peri/intra-tumoral inflammation.
Aim 3: We will evaluate the changing influence of excess adiposity on VAT-inflammation and tumor tissue inflammation over the life course, accounting for age of exposure to excess adiposity, and assessing the public health relevance of study findings using target trial emulation with G-computation and marginal structural modelling. ► We hypothesize that lifetime excess adiposity early in the life course is associated with lower VAT-inflammation and tumor inflammation, whereas excess adiposity later in adulthood is associated with greater VAT-inflammation and tumor inflammation, and that findings will inform risk stratification and high-risk men targeted with aggressive lifestyle and/or pharmacological interventions will demonstrate reduced PCa risk.
Impact: If confirmed, our free T-VAT inflammation hypothesis will largely explain many of the currently conflicting features of the epidemiology of adiposity and PCa, and (1) help establish obesity as a new risk factor for PCa, (2) provide a basis for risk prediction based on anthropometric patterns over the life course, which (3) identify high-risk men who can be targeted for screening or lifestyle interventions.

Fred Tabung (The Ohio State University College of Medicine and Comprehensive Cancer Center)