Cell lines are commonly used as cancer models. The tissue of origin provides context for understanding biological mechanisms and predicting therapy response. We therefore systematically examined whether cancer cell lines exhibit features matching the presumed cancer type of origin. Gene expression and DNA methylation classifiers trained on ~9000 tumors identified 35 (of 614 examined) cell lines that better matched a different tissue or cell type than the one originally assigned. Mutational patterns further supported most reassignments. For instance, cell lines identified as originating from the skin often exhibited a UV mutational signature. We cataloged 366 “golden set” cell lines in which transcriptomic and epigenomic profiles strongly resemble the cancer type of origin, further proposing their assignments to subtypes. Accounting for the uncertain tissue of origin in cell line panels can change the interpretation of drug screening and genetic screening data, revealing previously unknown genomic determinants of sensitivity or resistance.

细胞系通常用作癌症模型。起源组织为理解生物学机制和预测治疗反应提供了背景。因此，我们系统地检查了癌细胞系是否表现出与推测的癌症类型相匹配的特征。对约 9000 个肿瘤进行训练的基因表达和 DNA 甲基化分类器确定了 35 个（检查的 614 个）细胞系，这些细胞系与最初指定的组织或细胞类型更好地匹配。突变模式进一步支持大多数重新分配。例如，被确定为源自皮肤的细胞系通常表现出紫外线突变特征。我们对 366 个“黄金组”细胞系进行了编目，其中转录组和表观基因组谱与癌症起源类型非常相似，进一步提出了它们对亚型的分配。