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Background: We previously demonstrated an association of age and acculturation with oral microbiota among non-smoking women enrolled in a Texas cohort of first and second generation immigrants of Mexican origin. Given the increasing evidence that the oral microbiome is involved in obesity, diabetes and cancer risk, as well as the lack of data in Mexican Americans, we prospectively investigated baseline oral microbiota profiles in relation to all-cancer incidence. Methods: We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 369 non-smoking women, aged 20-78 years, enrolled in the MD Anderson Mano a Mano Mexican American (MA) cohort study. Using Dirichlet multinomial mixtures (DMM) modeling, we previously identified three microbial communities or clusters in our sample uniquely characterized by Streptococcus, Fusobacterium and Prevotella. We evaluated within (alpha) and between sample (beta) diversity by incident cancer status and applied Linear Discriminant Analysis (LDA) Effect Size analysis (LEfSe) to assess differentially abundant taxa. Results: Over 8.9 median years of follow-up, 31 incident cancer cases were identified and verified with the Texas Cancer Registry. In addition to advanced age and higher acculturation, a prior history of cardiovascular disease and multiple cardiometabolic risk factors (obesity, diabetes, high cholesterol, hypertension) were associated with higher all-cancer incidence in this subset of non-smoking women. With the exception of country of birth and following adjustment for age, none of these were strongly associated with the oral microbiome. Higher overall diversity of the oral microbiota, as assessed by Shannon diversity index, was observed among women diagnosed with cancer over follow-up, as compared to those who were not (age-adjusted Pdiff=0.0003). We observed potentially distinct biological communities, as measured by weighted UniFrac distance (Pdiff =0.001), and several differentially abundant taxa by incident cancer status. Fusobacterium, Campylobacter, Prevotella, Dialister and Atopobium were higher among women who developed cancer, while Streptococcus was enriched among women who did not develop cancer (LDA>=3, P Conclusions: To our knowledge, this is the first look at oral microbiota and cancer risk in Mexican American women. Our findings support the potential of the more readily accessible oral microbiota as a promising biomarker of cancer risk in non-smoking women. Citation Format: Xiaotao Zhang, Kristi L. Hoffman, Qiong Dong, Kplola Y. Elhor Gbito, Shine Chang, Joseph Petrosino, Carrie R. Daniel-MacDougall. Baseline oral microbiota profiles associated with all-cancer incidence in a cohort of non-smoking Mexican American women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1121.