Integration of multi-omics data to unveil the molecular landscape and role of piRNAs in early-onset colorectal cancer

作者：Siyun Zhou, Lili Yu, Jianhui Zhao, Qian Xiao, Jing Sun, Lijuan Wang, Yuan Zhou, Yadong Lu, Malcolm G. Dunlop, Evropi Τheodoratou, Honghe Zhang, Kefeng Ding, Xue Li · 发表于：BMC Medicine · 年份：2025 · DOI：10.1186/s12916-025-04074-2 · 被引用次数：6 · 研究领域：Ferroptosis and cancer prognosis、Genetic factors in colorectal cancer、Genomic variations and chromosomal abnormalities

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ...