Abstract：
Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity-a worldwide public health concern-is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas-Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.
摘要：
结直肠癌（CRC）是美国和全世界癌症相关死亡的第三大原因。肥胖是全球公共卫生问题，是包括CRC在内的癌症的已知危险因素。然而,CRC与肥胖之间联系的潜在机制尚未完全阐明,部分原因是CRC的分子异质性.我们假设肥胖以共有分子亚型(CMS)依赖性方式调节CRC。从癌症基因组图谱-结肠腺癌(TCGA-COAD)数据库获得232名患者的RNA-seq数据和相关肿瘤和患者特征,包括体重和身高数据。使用CMScallerR软件包将肿瘤样本分类到四个CMS中；计算体重指数（BMI）并将其分类为正常，超重,和肥胖。我们观察到BMI类别之间的CMS分类存在显着差异。肥胖和超重样本与正常样本之间的差异表达基因（DEGs）在CMS中有所不同，和相关的预后分析表明,DEGs对生存有不同的关联.使用基因集富集分析，我们发现肥胖和超重样本与CMS正常样本之间的Hallmark基因集富集存在差异.我们构建了蛋白质-蛋白质相互作用网络，并观察了每个CMS的肥胖调节中心基因的差异。最后,我们分析并发现了肥胖和超重样本与正常样本之间的药物敏感性预测差异。我们的发现支持肥胖以CMS特异性方式影响CRC肿瘤转录组。此处报道的可能关联是初步的，需要使用体外和动物模型进行验证，以检查基因和途径的CMS依赖性。一旦验证，与肥胖相关的基因和途径可能代表以CMS依赖性方式治疗结肠癌的新治疗靶标。
