Obesity, classified by BMI (body weight/height2) is associated with higher risk of at least 12 cancers in postmenopausal women. Yet, BMI is a particularly blunt tool to understand the etiology of body composition contributions to cancer risk, and actually identify causal targets for intervention and cancer prevention. This is because BMI does not address the central hypothesis underlying the obesity-cancer association- that higher levels of abdominal visceral adipose tissue (VAT), which accumulates to a greater extent post menopause in the intra-abdominal cavity, drives the pathophysiology of obesity-related cancers via its role in inflammatory, metabolic, 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 soft tissue, LST), which has the potential to ameliorate dysfunction in these VAT driven pathways. Nevertheless, muscle has not been examined in relation to tumorigenesis, though it is emerging as an important component of survival. Despite the increase in obesity-related cancers and burgeoning research triangulated to inform the carcinogenic VAT hypothesis, the hypothesis is effectively untested. This proposal is of particular significance because the evidence base lacks sufficiently powered studies that are able to examine both detailed body composition and anthropometric exposures simultaneously in relation to cancer incidence and mortality. This reflects the historical prohibitive cost, availability, and radiation exposure associated with measuring specific abdominal 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 from existing DXA scans within the well-characterized Women's Health Initiative (WHI). We will similarly measure abdominal LST, to complement the total body measures available, in this prospective cohort of nearly 11,000 women with repeated DXA measurements at baseline and 3, 6 and 9 years later. We will examine how levels of 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 in relation 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 other tissues, is a risk factor, for all cancers. This wholly unique dataset with adjudicated outcomes over 25 years will provide novel insight into the etiological role of the aforementioned abdominal adipose tissue depots and LST in cancer risk and cancer mortality. We will use a comprehensive, rigorous analytic approach to address our aims and hypotheses. The study will inform and alter clinical practice beyond the anticipated impact that the results from our aims portend. In sum, we will address a major knowledge gap of both clinical and

Public Health Relevance

This study will use innovative software to derive new abdominal lean soft tissue data from historic dual-energy X-ray absorptiometry scans in the Women's Health Initiative (approx. 11,000 women with repeat scans over 9 years; 25 years of follow-up) and leverage recently derived abdominal visceral and subcutaneous adipose tissue values obtained using the same innovative software. These new data will be used to address essential unanswered questions on the topic of obesity and cancer by quantifying the relationship between these measures with risk of cancer in postmenopausal women, and cancer related deaths as they age. This study will inform etiological understanding, improve risk assessment, and, most importantly, enhance our ability to target interventions and cancer prevention efforts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA253302-01
Application #
10050524
Study Section
Cancer, Heart, and Sleep Epidemiology A Study Section (CHSA)
Program Officer
Sauter, Edward Richard
Project Start
2020-07-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Arizona
Department
Nutrition
Type
Earth Sciences/Resources
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721