PO.CL12.03 · 临床研究
早发性结直肠癌中独特的基因组及通路层面改变：一项大规模韩国队列分析
Distinct genomic and pathway-level alterations in early-onset colorectal cancer: A large-scale Korean cohort analysis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：早发性结直肠癌（EOC）在全球范围内发病率不断上升，但其在亚洲人群中的基因组特征仍未得到充分描述。了解EOC与传统发病年龄结直肠癌（TOC）之间的分子差异，对于阐明年龄相关的肿瘤生物学至关重要。
患者与方法：采用靶向下一代测序技术，对1,675例全国范围内的结直肠癌患者（2017-2021年）的基因组图谱进行了分析。EOC定义为诊断年龄≤50岁，TOC定义为>50岁。采用基于R的分析流程比较EOC与TOC之间的突变频率、突变谱、通路富集及共现模式，包括经FDR校正的Fisher精确检验以及maftools。进行了功能分析和蛋白-蛋白相互作用分析（DAVID、Metascape/MCODE）以识别富集通路，并额外评估了HRD相关基因的无义和移码功能缺失变异。
结果：在1,675例患者（428例EOC；1,247例TOC）中，EOC表现出更高比例的TMB-high肿瘤（18% vs. 12%，p = 0.009）和MSI-high肿瘤（5.1% vs. 2.2%，p = 0.003），提示年轻个体中超突变表型的患病率更高。EOC在SMAD4、FAT3和KMT2D中的突变率也更高，与TOC相比各自增加约3-4%。相比之下，经典的结直肠癌驱动基因如APC、KRAS、TP53及WNT相关基因在TOC中改变更为频繁。在突变谱分析中，EOC表现出略高的转换/颠换比，与更大的内在基因组不稳定性相一致。通路分析显示EOC中NOTCH、PI3K、Hippo、TGF-beta、细胞周期及MYC通路富集，而TOC中RTK-RAS和WNT通路占主导地位。九十一个基因在EOC中显示出显著更高的突变频率（FDR < 0.05）。HRD相关基因（BRCA1/2、PALB2、RAD51C/D、ATM、CHEK2）的功能缺失突变在EOC中也更为频繁（11.4% vs. 8%），支持同源重组缺陷在早发性疾病中的更大作用。共现网络分析揭示了EOC特异性簇，涉及染色质重塑和DNA修复模块，包括一个占主导地位的DNA修复超级簇（log10(P) = -16.5至-18.6），以及富集的表观遗传和转录调控模块。
结论：EOC表现出独特的基因组及通路层面特征，包括更高的基因组不稳定性以及染色质重塑和DNA修复的富集。这些发现表明EOC代表结直肠癌中一种生物学上独特的亚型，可能受益于针对特定年龄或针对HRD的治疗策略。未来将胚系测序与体细胞图谱相结合的研究将有助于更全面地阐明EOC的年龄相关分子特征。
查看英文原文 English abstract
Background: Early-onset colorectal cancer (EOC) is rising in incidence globally, yet its genomic landscape in Asian populations remains inadequately characterized. Understanding molecular differences between EOC and traditional-onset colorectal cancer (TOC) is essential for clarifying age-related tumor biology.
Patients and methods: Genomic profiles from 1,675 nationwide colorectal cancer patients (2017-2021) were analyzed using targeted next-generation sequencing. EOC was defined as diagnosis at ≤50 years and TOC as >50 years. Mutational frequencies, spectra, pathway enrichment, and co-occurrence patterns were compared between EOC and TOC using R-based pipelines, including Fisher's exact test with FDR adjustment and maftools. Functional and protein-protein interaction analyses (DAVID, Metascape/MCODE) were performed to identify enriched pathways, and HRD-associated genes were additionally assessed for nonsense and frameshift loss-of-function variants.
Results: Among 1,675 patients (428 EOC; 1,247 TOC), EOC showed higher rates of TMB-high tumors (18% vs. 12%, p = 0.009) and MSI-high tumors (5.1% vs. 2.2%, p = 0.003), indicating a greater prevalence of hypermutated phenotypes in younger individuals. EOC also demonstrated higher mutation rates in SMAD4, FAT3, and KMT2D , each increased by approximately 3-4% compared with TOC. In contrast, classical colorectal cancer drivers such as APC, KRAS, TP53 , and WNT -related genes were more frequently altered in TOC. In mutational spectrum analysis, EOC exhibited a modestly higher transition-to-transversion ratio, consistent with greater intrinsic genomic instability. Pathway analysis demonstrated enrichment of NOTCH, PI3K, Hippo, TGF-beta, cell-cycle, and MYC pathways in EOC, while RTK-RAS and WNT pathways predominated in TOC. Ninety-one genes showed significantly higher mutation frequencies in EOC (FDR < 0.05). Loss-of-function mutations in HRD-related genes ( BRCA1/2, PALB2, RAD51C/D, ATM, CHEK2 ) were also more frequent in EOC (11.4% vs. 8%), supporting the greater contribution of homologous recombination defects in early-onset disease. Co-occurrence network analyses revealed EOC-specific clusters involving chromatin remodeling and DNA repair modules, including a dominant DNA repair supercluster (log 10 (P) = -16.5 to -18.6), alongside enriched epigenetic and transcriptional regulation modules.
Conclusions: EOC exhibits distinct genomic and pathway-level characteristics, including higher genomic instability and enrichment of chromatin remodeling and DNA repair. These findings indicate that EOC represents a biologically unique subtype of colorectal cancer that may benefit from age-specific or HRD-targeted therapeutic strategies. Future work integrating germline sequencing with somatic profiles will help more comprehensively clarify the age-related molecular features of EOC.
利益披露 Disclosure
A. Lim, None..
M. Kim, None.