Devall Matthew A, Eaton Stephen, Ali Mourad W, Powell Steven M, Li Li, Casey Graham
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA.
Cancers (Basel). 2022 Aug 26;14(17):4138. doi: 10.3390/cancers14174138.
Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.
近几十年来，早发性结直肠癌（EOCRC）的发病率有所上升。虽然将常规结肠镜检查的推荐年龄降至45岁可能会减轻这一负担，但这些措施并未针对在该年龄之前发生结直肠癌的患者。需要采取额外措施来识别结直肠癌的高危个体。为了更好地定义结直肠癌发生之前的转录组事件，我们对来自7名健康人和6名家族性腺瘤性息肉病（FAP）患者的结肠类器官进行了RNA测序分析。这导致鉴定出2635个显著差异表达基因（FDR<0.05）。通过对公开可用数据集的二次分析，我们发现这些基因在FAP结直肠癌和非遗传性结直肠癌数据集中也富含显著基因，包括一组EOCRC特有的基因。通过将FAP结肠类器官暴露于为期三天的乙醇处理，我们发现两个与EOCRC相关的基因也是结直肠癌相关生活方式因素的靶点。我们的数据为结肠上皮细胞中结直肠癌发生的潜在早期机制提供了独特的见解，这可能为患者监测提供生物标志物。我们还展示了可改变的生活方式因素如何进一步改变与EOCRC相关的基因，进一步支持了这样的假设：这些因素是EOCRC发病率增加的重要因素。
