用对比学习对43种癌症按突变特征聚类,发现新分型规律。
MS-ConTab: Multi-Scale Contrastive Learning of Mutation Signatures for Pan Cancer Representation and Stratification
- 构建基因级与染色体级双突变谱,用TabNet编码
- 43种癌症聚类结果符合已知突变机制与组织来源
- 首个将对比学习用于癌症类型级聚类的方法
理解泛癌突变图谱有助于揭示肿瘤发生的分子机制。尽管患者层面的机器学习已被广泛用于识别肿瘤亚型,但基于共享分子特征对整个癌症类型进行分组的队列级聚类,仍主要依赖传统统计方法。本研究提出一种新的无监督对比学习框架,基于COSMIC数据库的编码突变数据,对43种癌症类型进行聚类。针对每种癌症类型,构建两种互补的突变谱:基因级谱(捕捉最常突变基因中的核苷酸替换模式)和染色体级谱(表示染色体上标准化的替换频率)。使用TabNet编码器对双视图进行编码,并通过多尺度对比学习目标(NT-Xent损失)优化,以学习统一的癌症类型嵌入。结果显示,所得潜在表示能生成具有生物学意义的癌症类型聚类,与已知突变过程及组织起源一致。本工作首次将对比学习应用于队列级癌症聚类,提供了一种可扩展且可解释的突变驱动癌症亚型划分框架。
原文摘要 · Abstract (English)
Motivation. Understanding the pan-cancer mutational landscape offers critical insights into the molecular mechanisms underlying tumorigenesis. While patient-level machine learning techniques have been widely employed to identify tumor subtypes, cohort-level clustering, where entire cancer types are grouped based on shared molecular features, has largely relied on classical statistical methods. Results. In this study, we introduce a novel unsupervised contrastive learning framework to cluster 43 cancer types based on coding mutation data derived from the COSMIC database. For each cancer type, we construct two complementary mutation signatures: a gene-level profile capturing nucleotide substitution patterns across the most frequently mutated genes, and a chromosome-level profile representing normalized substitution frequencies across chromosomes. These dual views are encoded using TabNet encoders and optimized via a multi-scale contrastive learning objective (NT-Xent loss) to learn unified cancer-type embeddings. We demonstrate that the resulting latent representations yield biologically meaningful clusters of cancer types, aligning with known mutational processes and tissue origins. Our work represents the first application of contrastive learning to cohort-level cancer clustering, offering a scalable and interpretable framework for mutation-driven cancer subtyping.
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