ABSTRACTObesity classified by BMI (body weight/height2) is associated with higher risk of at least 12 cancers inpostmenopausal women. Yet BMI is a particularly blunt tool to understand the etiology of body compositioncontributions to cancer risk and actually identify causal targets for intervention and cancer prevention. This isbecause BMI does not address the central hypothesis underlying the obesity-cancer association- that higherlevels of abdominal visceral adipose tissue (VAT) which accumulates to a greater extent post menopause inthe intra-abdominal cavity drives the pathophysiology of obesity-related cancers via its role in inflammatorymetabolic and immune dysfunction - hallmarks of cancer. Whereas adipose tissue just under the skin(subcutaneous SAT) may even be benign. BMI also does not delineate between fat and muscle (i.e. lean softtissue LST) which has the potential to ameliorate dysfunction in these VAT driven pathways. Neverthelessmuscle has not been examined in relation to tumorigenesis though it is emerging as an important componentof survival. Despite the increase in obesity-related cancers and burgeoning research triangulated to inform thecarcinogenic VAT hypothesis the hypothesis is effectively untested. This proposal is of particular significancebecause the evidence base lacks sufficiently powered studies that are able to examine both detailed bodycomposition and anthropometric exposures simultaneously in relation to cancer incidence and mortality. Thisreflects the historical prohibitive cost availability and radiation exposure associated with measuring specificabdominal adipose tissue depots by CT and MRI. Recent advances in Dual Energy X-Ray Absorptiometry(DXA) technology validated against CT and MRI have allowed us to quantify abdominal VAT and SAT fromexisting DXA scans within the well-characterized Women's Health Initiative (WHI). We will similarly measureabdominal LST to complement the total body measures available in this prospective cohort of nearly 11000women with repeated DXA measurements at baseline and 3 6 and 9 years later. We will examine how levelsof abdominal VAT SAT and LST as well as total body composition and anthropometry associate with obesity-related cancer incidence and mortality. Moreover we will examine these body composition measures inrelation to lung cancer (not classified as obesity-related) to address anomalies in the literature i.e. BMI(inverse) and waist (positive) associations with lung cancer. We hypothesize that VAT in the context of othertissues is a risk factor for all cancers. This wholly unique dataset with adjudicated outcomes over 25 years willprovide novel insight into the etiological role of the aforementioned abdominal adipose tissue depots and LSTin cancer risk and cancer mortality. We will use a comprehensive rigorous analytic approach to address ouraims and hypotheses. The study will inform and alter clinical practice beyond the anticipated impact that theresults from our aims portend. In sum we will address a major knowledge gap of both clinical and