ABSTRACT: Obesity is a risk factor for?>?13 cancer sites, although it is unknown whether there is a common mechanism across sites. Evidence suggests a role for impaired branched-chain amino acid (BCAAs; isoleucine, leucine, valine) metabolism in obesity, insulin resistance, and immunity; thus, we hypothesized circulating BCAAs may be associated with incident obesity-related cancers. We analyzed participants in the prospective Women's Health Study without a history of cancer at baseline blood collection (N?=?26,711, mean age?=?54.6 years [SD?=?7.1]). BCAAs were quantified via NMR spectroscopy, log-transformed, and standardized. We used Cox proportional regression models adjusted for age, race, smoking, diet, alcohol, physical activity, menopausal hormone use, Body Mass Index (BMI), diabetes, and other risk factors. The endpoint was a composite of obesity-related cancers, defined per the International Agency for Research on Cancer 2016 report, over a median 24 years follow-up. Baseline BMI???30 kg/m2 compared with BMI 18.5-25.0 kg/m2 was associated with 23% greater risk of obesity-related cancers (n?=?2751 events; multivariable HR 1.23, 95% CI 1.11-1.37). However, BCAAs were not associated with obesity-related cancers (multivariable HR per SD?=?1.01 [0.97-1.05]). Results for individual BCAA metabolites suggested a modest association for leucine with obesity-related cancers (1.04 [1.00-1.08]), and no association for isoleucine or valine (0.99 [0.95-1.03] and 1.00 [0.96-1.04], respectively). Exploratory analyses of BCAAs with individual sites included positive associations between leucine and postmenopausal breast cancer, and isoleucine with pancreatic cancer. Total circulating BCAAs were unrelated to obesity-related cancer incidence although an association was observed for leucine with incident obesity-related cancer.
