Abstract B097: Molecular disparities between cancer patients with normal weight and excessive body fat

Abstract

Abstract Overweight and obesity, as measured by high body mass index (BMI), can have significant negative impacts on human health due to associated co-morbidities. Epidemiological data have demonstrated strong associations between overweight/obesity and 13 different types of cancer. However, the molecular features underlying the relationship between body weight and cancer remain poorly understood. In this study, we conducted a comprehensive analysis of molecular differences between patients with overweight/obesity and normal-weight patients across 14 different cancer types from The Cancer Genome Atlas (TCGA). By employing the propensity score weighting algorithm to balance confounding factors, we identified obesity-specific mutational features in multiple cancer types, such as a higher mutation burden in rectal cancer, biased mutational signatures, and overweight/obesity-specific significantly mutated genes in several cancer types. The biased mutation signatures are caused by the activity of AID/APOBEC family of cytidine deaminases and their contribution to DNA damage, ect, which suggest that obesity may contribute to the development of cancer by promoting the accumulation of specific types of mutations. Most of these biased genes have not been reported as significantly mutated genes in previous TCGA large cohort, implying these biased genes may be due to the environment of excessive body fat. We also found that differential expression genes (DEGs) and dysmethylated genes in overweight and obese tumors were predominantly upregulated and enriched in inflammatory and hormone-related pathways. These DEGs were significantly associated with survival rates in various cancer types, highlighting the impact of excessive body fat on gene expression profiles and clinical outcomes in cancer patients. Interestingly, while high BMI seemed to have a negative impact on most cancer types, it may be beneficial to endometrial cancers, as reflected by normal weight-biased mutational and gene expression patterns, suggesting the presence of an "obesity paradox" in this context. Moreover, our analysis revealed that excessive body fat significantly impacted the tumor microenvironment by altering immune cell infiltration, emphasizing the importance of understanding the complex interplay between obesity and immune response in cancer progression and treatment. Overall, our results provide the most comprehensive understanding of the molecular differences including mutational patterns, gene expression, and immune features between normal-weight and overweight/obese cancer patients. Such systematic understanding of the molecular basis for body weight disparities in multiple cancer types may provide critical insights into the future development of precision cancer therapy for cancer patients with overweight/obesity. Citation Format: Fengyuan Huang, Peng Xu, Zongliang Yue, Yuwei Song, Kaili Hu, Xinyang Zhao, Min Gao, Zechen Chong. Molecular disparities between cancer patients with normal weight and excessive body fat [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B097.