Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Cell Rep Med. 2023 Mar 21;4(3):100974. doi: 10.1016/j.xcrm.2023.100974. Epub 2023 Mar 14.
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.
早发性结直肠癌（EOCRC）的发病率正在上升，其定义为诊断年龄在 50 岁以下，但与一般结直肠癌不同的是，其病因具有异质性，目前仍未确定。我们最初对来自中国 CRC 队列的 79 名患者的肿瘤进行了基因组、表观基因组、转录组和蛋白质组分析。此外，我们还从国际癌症基因组联盟中国队列和癌症基因组图谱欧洲队列中获得了另外 126 名 EOCRC 患者的数据。我们观察到早发性肿瘤具有较高的肿瘤突变负担；通过突变特征 3 和多层次通路富集，增加了 DNA 修复特征；DNA 甲基化和体细胞拷贝数改变对基因表达的强烈干扰；以及上调的免疫浸润，表现为免疫表型下的热肿瘤。值得注意的是，LMTK3 表现出祖先突变差异，可能是一种功能性调节剂和生物标志物，驱动 EOCRC 发展和免疫治疗中的分子改变。这项综合组学研究为 CRC 的精准肿瘤学提供了有价值的知识。
