PO.CL12.03 · 临床研究
在西班牙裔/拉丁裔结直肠癌中鉴定出的表观遗传聚类揭示新的分子亚型
Epigenetic clusters identified in Hispanic/LatinX colorectal cancers reveal novel molecular subtypes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：结直肠癌（CRC）的发病率和死亡率在西班牙裔/拉丁裔（HL）人群中呈上升趋势，但他们在基因组研究中仍代表性不足。因此，HL CRC是否具有独特的表观遗传或生物学特征尚不清楚。我们通过使用全基因组DNA甲基化对HL CRC肿瘤进行分析，并将这些数据与匹配的转录组和基因组数据集整合，从而填补了这一空白。
方法：我们使用Illumina EPIC v2芯片为104例HL CRC肿瘤生成DNA甲基化谱。RNA-seq（n=92）和全外显子组测序（WES；n=89）可用于整合分析。TCGA的非西班牙裔白人（NHW）CRC作为参考队列。使用八个经典CIMP标志物（MLH1、IGF2、CACNA1G、NEUROG1、RUNX3、SOCS1、CRABP1、CDKN2A）的启动子甲基化值分配CIMP状态。使用变异性最高的CpG的无监督聚类来定义甲基化亚型。通过将CpG汇总为癌症相关通路中的基因背景评分来进行通路解读。匹配的RNA-seq和WES数据用于表征每种亚型的转录和突变特征，并验证DNA甲基化通路解读。分配了CMS分类和MSI状态以供比较。
结果：HL CRC中的CIMP模式与TCGA中的NHW肿瘤明显不同。仅有1%的HL MSI肿瘤为CIMP-H（相比之下NHW MSI CRC为7.1%），11%为CIMP-0（相比之下NHW为3.4%），表明MSI与CIMP-H状态的解偶联。无监督聚类鉴定出六种新的甲基化定义亚型（HL-C1至HL-C6），具有独特的免疫、基质、代谢和表观遗传特征。这些亚型在诊断时的平均年龄和整体甲基化方面也有所不同：HL-C1（58.7岁，beta=0.493）、HL-C2（51.2岁，beta=0.358）、HL-C3（60.1岁，beta=0.428）、HL-C4（51.9岁，beta=0.222）、HL-C5（52.8岁，beta=0.460）和HL-C6（44.5岁，beta=0.608）。与RNA-seq的整合证实了重叠样本间通路激活的一致性。体细胞突变进一步区分了亚型：TP53突变在HL-C6中减少（37.5%，而其他聚类约为66%），而MLH1突变富集（12.5%）。CMS分配未能重现这六种HL特异性亚型。
结论：HL CRC表现出现有CIMP或CMS框架未能捕捉到的分子特征。此处鉴定的独特甲基化亚型为HL CRC生物学提供了新见解，并为完善该人群未来的分子研究奠定了基础。
查看英文原文 English abstract
Introduction: Colorectal cancer (CRC) incidence and mortality are rising among Hispanic/LatinX (HL) individuals, yet they remain underrepresented in genomic studies. As a result, it is unknown whether HL CRCs harbor distinct epigenetic or biological features. We addressed this gap by profiling HL CRC tumors using genome-wide DNA methylation and integrating these data with matched transcriptomic and genomic datasets.
Methods: We generated DNA methylation profiles for 104 HL CRC tumors using the Illumina EPIC v2 array. RNA-seq (n=92) and whole-exome sequencing (WES; n=89) were available for integrative analyses. TCGA non-Hispanic White (NHW) CRCs served as a reference cohort. CIMP status was assigned using promoter methylation values for eight canonical CIMP markers (MLH1, IGF2, CACNA1G, NEUROG1, RUNX3, SOCS1, CRABP1, CDKN2A). Unsupervised clustering of the top most variable CpGs was used to define methylation subtypes. Pathway interpretation was performed by summarizing CpGs into gene-context scores across cancer related pathways. Matched RNA-seq and WES data were used to characterize transcriptional and mutational features of each subtype and validate DNA methylation pathway interpretation. CMS classifications, MSI status were assigned for comparison.
Results: CIMP patterns in HL CRCs differed markedly from NHW tumors in TCGA. Only 1% of HL MSI tumors were CIMP-H (vs. 7.1% in NHW MSI CRCs), and 11% were CIMP-0 (vs. 3.4% in NHW), indicating a decoupling of MSI and CIMP-H status. Unsupervised clustering identified six novel methylation-defined subtypes (HL-C1 to HL-C6) with distinct immune, stromal, metabolic, and epigenetic features. These subtypes also differed by mean age at diagnosis and global methylation: HL-C1 (58.7y, beta=0.493), HL-C2 (51.2y, beta=0.358), HL-C3 (60.1y, beta=0.428), HL-C4 (51.9y, beta=0.222), HL-C5 (52.8y, beta=0.460), and HL-C6 (44.5y, beta=0.608). Integration with RNA-seq confirmed concordant pathway activation across overlapping samples. Somatic mutations further distinguished subtypes: TP53 mutations were reduced in HL-C6 (37.5% vs. ~66% in other clusters), while MLH1 mutations were enriched (12.5%). CMS assignments did not recapitulate these six HL-specific subtypes.
Conclusion: HL CRCs display molecular features not captured by existing CIMP or CMS frameworks. The distinct methylation subtypes identified here offer new insight into HL CRC biology and provide a foundation for refining future molecular studies in this population.
利益披露 Disclosure
S. Rajpara, None..
V. Yamamoto, None..
C. Chavez, None..
J. D. Carpten, None..
D. W. Craig, None..
H. Lenz, None..
B. Salhia, None.