PDF(Pubmed)
Abstract：
Numerous demographic factors have been associated with colorectal cancer (CRC) risk. To better define biological mechanisms underlying these associations, we performed RNA sequencing of stem-cell-enriched organoids derived from the healthy colons of seven European Americans and eight African Americans. A weighted gene co-expression network analysis was performed following RNA sequencing. Module-trait relationships were determined through the association testing of each module and five CRC risk factors (age, body mass index, sex, smoking history, and race). Only modules that displayed a significantly positive correlation for gene significance and module membership were considered for further investigation. In total, 16 modules were associated with known CRC risk factors (p < 0.05). To contextualize the role of risk modules in CRC, publicly available RNA-sequencing data from TCGA-COAD were downloaded and re-analyzed. Differentially expressed genes identified between tumors and matched normal-adjacent tissue were overlaid across each module. Loci derived from CRC genome-wide association studies were additionally overlaid across modules to identify robust putative targets of risk. Among them, MYBL2 and RXRA represented strong plausible drivers through which cigarette smoking and BMI potentially modulated CRC risk, respectively. In summary, our findings highlight the potential of the colon organoid system in identifying novel CRC risk mechanisms in an ancestrally diverse and cellularly relevant population.
摘要：
许多人口统计学因素与结直肠癌（CRC）风险相关。为了更好地定义这些关联的生物学机制，我们对来自7名欧洲裔美国人和8名非洲裔美国人健康结肠的富含干细胞的类器官进行了RNA测序.在RNA测序之后进行加权基因共表达网络分析。通过对每个模块和五个CRC风险因素（年龄，身体质量指数,性别,吸烟史,和种族）。仅考虑对基因显著性和模块成员资格表现出显着正相关的模块进行进一步研究。总的来说,16个模块与已知的CRC危险因素相关(p<0.05)。为了说明风险模块在CRC中的作用，下载并重新分析TCGA-COAD公开的RNA测序数据.在肿瘤和匹配的正常邻近组织之间鉴定的差异表达基因在每个模块上覆盖。另外将来自CRC全基因组关联研究的基因座覆盖在模块中以识别可靠的推定风险靶标。其中,MYBL2和RXRA代表了强有力的似是而非的驱动因素，通过这些驱动因素，吸烟和BMI可能会调节CRC风险，分别。总之,我们的研究结果强调了结肠类器官系统在识别祖先多样且细胞相关的人群中新型CRC风险机制方面的潜力.
