Marx Olivia M, Mankarious Marc M, Koltun Walter A, Yochum Gregory S
Koltun and Yochum Laboratory, Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University College of Medicine, Hershey, PA, United States.
Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, United States.
Front Oncol. 2024 Apr 11;14:1365762. doi: 10.3389/fonc.2024.1365762. eCollection 2024.
The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC.
We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens.
We identified an eight-gene signature in EOCRC comprised of , , , , , , and , from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, . Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens.
Our transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets.
在过去几十年中，结直肠癌（CRC）在年轻个体中的发病率一直在稳步上升，其原因尚未完全明确。识别早发性结直肠癌（EOCRC，年龄<50岁）患者与晚发性结直肠癌（LOCRC，年龄>50岁）患者基因表达谱或转录组的差异，是了解区分EOCRC的分子和遗传特征的一种方法。
我们进行了RNA测序（RNA-seq），以表征来自EOCRC（n=21）和LOCRC（n=22）患者的肿瘤与配对的肿瘤旁未受累（正常）结肠段的转录组。EOCRC和LOCRC队列在人口统计学和临床特征方面进行了匹配。我们使用癌症基因组图谱结肠腺癌（TCGA-COAD）数据库进行验证。我们使用了一系列计算和生物信息学工具来识别EOCRC特异性差异表达基因、分子途径、预测的细胞群体、差异基因剪接事件和预测的新抗原。
我们在EOCRC中鉴定出一个由[具体八个基因名称]组成的八基因特征，据此开发了一个预测CRC患者总体生存的评分。在正常组织和肿瘤中鉴定出的所有基因上，细胞类型反卷积分析预测EOCRC与LOCRC中免疫和非免疫群体的丰度存在差异。基因集富集分析确定EOCRC中剪接机制的表达增加。我们进一步发现了可变剪接（AS）事件的差异，包括长链非编码RNA[具体名称]中的一个事件。对AS的进一步分析发现了七个特定于EOCRC的事件，这些事件编码潜在的新抗原。
我们的转录组分析确定了EOCRC特有的遗传和分子特征，这可能为未来的筛查、预后指标的开发和新的药物靶点提供信息。
