Zhou Siyun, Yu Lili, Zhao Jianhui, Xiao Qian, Sun Jing, Wang Lijuan, Zhou Yuan, Lu Yadong, Dunlop Malcolm G, Theodoratou Evropi, Zhang Honghe, Ding Kefeng, Li Xue
Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
BMC Med. 2025 Apr 29;23(1):250. doi: 10.1186/s12916-025-04074-2.
The incidence of early-onset colorectal cancer (EOCRC) (< 50 years) has been steadily rising, with a parallel increase in metastatic and invasive cases. To elucidate the molecular mechanisms underlying this aggressive phenotype, we performed comprehensive multi-omics profiling to delineate the distinct features of EOCRC, with a focus on key drivers of metastatic and invasive potential.
We initially characterized the genome, epigenome, and transcriptome of tumors from 515 (69 EOCRC and 446 late-onset CRC [LOCRC]) cases in The Cancer Genome Atlas. Key candidate molecules were further validated using RNA-seq and scRNA-seq data. Multi-omics profiling revealed PIWIL1/piRNA as a hallmark of EOCRC, with further validation through in vitro functional assays, transcriptomic profiling, and Kaplan-Meier survival analysis.
EOCRC demonstrated a mutational landscape similar to that of LOCRC, with comparable oncogenic driver mutations and somatic copy-number alterations. However, EOCRC exhibited a higher frequency of deletion in chromosomes 6, 15, and 19 regions, along with metabolic reprogramming favoring aerobic glycolysis and lipid metabolism. Integrative transcriptomic and DNA methylation analyses identified six EOCRC-specific molecules, including PIWIL1. Notably, PIWIL1 was mainly expressed in epithelial cells, with lower expression in EOCRC versus LOCRC. Its downstream piRNAs (FR019019, FR019089, and FR132045) were also downregulated in EOCRC. Functional experiments demonstrated that FR019089/FR019019 overexpression suppressed migration and invasion. Clinically, low FR019089 levels correlated with significantly shorter progression-free and overall survival in EOCRC patients. Additionally, downstream pathways of FR019089 and FR019019 overexpression were enriched in anti-cancer-related signaling pathways.
Our multi-omics approach yields novel insights into the molecular underpinnings of EOCRC and we characterize the role of PIWIL1-associated piRNAs in modulating EOCRC metastasis and invasion. FR019089 shows promise as a prognostic biomarker with potential clinical utility in the risk stratification and management of EOCRC patients.
早发性结直肠癌（EOCRC，年龄<50岁）的发病率一直在稳步上升，转移和侵袭性病例也相应增加。为了阐明这种侵袭性表型背后的分子机制，我们进行了全面的多组学分析，以描绘EOCRC的独特特征，重点关注转移和侵袭潜能的关键驱动因素。
我们首先对癌症基因组图谱中515例病例（69例EOCRC和446例晚发性结直肠癌[LOCRC]）的肿瘤基因组、表观基因组和转录组进行了特征分析。使用RNA测序和单细胞RNA测序数据进一步验证关键候选分子。多组学分析显示PIWIL1/piRNA是EOCRC的一个标志，并通过体外功能试验、转录组分析和Kaplan-Meier生存分析进行了进一步验证。
EOCRC表现出与LOCRC相似的突变格局，具有相当的致癌驱动基因突变和体细胞拷贝数改变。然而，EOCRC在6号、15号和19号染色体区域的缺失频率更高，同时伴有有利于有氧糖酵解和脂质代谢的代谢重编程。综合转录组和DNA甲基化分析确定了六个EOCRC特异性分子，包括PIWIL1。值得注意的是，PIWIL1主要在上皮细胞中表达，在EOCRC中的表达低于LOCRC。其下游的piRNAs（FR019019、FR019089和FR132045）在EOCRC中也下调。功能实验表明，FR019089/FR019019的过表达抑制了迁移和侵袭。临床上，低FR019089水平与EOCRC患者显著缩短的无进展生存期和总生存期相关。此外FR019089和FR019019过表达的下游通路在抗癌相关信号通路中富集。
我们的多组学方法为EOCRC的分子基础提供了新的见解，并且我们阐述了PIWIL1相关piRNAs在调节EOCRC转移和侵袭中的作用。FR019089有望作为一种预后生物标志物，在EOCRC患者的风险分层和管理中具有潜在的临床应用价值。
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