Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer

• Published in: Cell reports. Medicine Vol. 4; no. 3; p. 100974
• Main Authors: Du, Mulong, Gu, Dongying, Xin, Junyi, Peters, Ulrike, Song, Mingyang, Cai, Guoshuai, Li, Shuwei, Ben, Shuai, Meng, Yixuan, Chu, Haiyan, Chen, Lianmin, Wang, Qianghu, Zhu, Lingjun, Fu, Zan, Zhang, Zhengdong, Wang, Meilin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2023; Elsevier
• Subjects: Advanced Basic Science; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; early-onset colorectal cancer; Humans; immunophenotype; LMTK3; Membrane Proteins - genetics; Middle Aged; multi-omics; Multiomics; Mutation; Precision Medicine; Protein Serine-Threonine Kinases - genetics; Transcriptome - genetics; multi-omics; LMTK3; early-onset colorectal cancer; immunophenotype
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.100974

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC. [Display omitted] •An integrative omics study of early-onset colorectal cancer in a Chinese cohort•Omics architecture supports early-onset tumorigenesis and therapeutic development•Mutational landscape varies by ancestry, and LMTK3 mutation has Chinese specificity•LMTK3 works at DNA repair process, immunophenotype, and drug target The molecular characterization of early-onset colorectal cancer remains undetermined. We report a multi-omics landscape of young colorectal tumors in a Chinese cohort. These profiles reveal distinct molecular alterations and immunophenotypes in early-onset tumorigenesis and provide an ancestry-specific LMTK3 as a modulator, biomarker, and therapeutic target for precision oncology.