Omics catalogue of lung adenocarcinoma cell lines

Cancer cells carry various types of aberrations at the levels of genome, epigenome and transcriptome. For future studies on the biological relevance of the aberrations and their mutual relations, we generated a multi-omics catalogue of 26 lung adenocarcinoma cell lines. By whole-genome sequencing, we detected SNVs and indels, copy number aberrations and chromosome rearrangements. We used RNA-Seq to examine whether those mutation-harboring genes are expressed in the corresponding cell lines or whether their expression levels are deviated between the cell lines. Also, we could detect known and novel abnormal transcripts, such as RET- and ALK-fusion transcripts and transcripts caused by splice site mutations. Similarly, target-captured bisulfite sequencing and ChIP-Seq analyses revealed epigenomic status in each cell line and their deviations. We integrated these multi-omics data to explain possible causes of the observed aberrant gene expressions, particular for the representative cancer-related genes. We unexpectedly found that the patterns of aberrations were highly diverse between genes; namely irregular chromatin status revealed by ChIP-Seq was the characteristic to the EGFR, while a large genomic deletion and hyper-DNA methylation in the promoter region were the most frequent for the CDKN2A gene. Our datasets, by complementing current whole-exome or whole-genome sequencing of clinical cancers, should lay valuable base for interpreting how various types of genomic and epigenomic aberration lead to aberrant transcriptomic appearances in cancers.

癌细胞在基因组、表观基因组与转录组层面均存在多种类型的畸变。为开展后续关于畸变的生物学关联及其相互作用机制的研究，我们构建了涵盖26株肺腺癌细胞系的多组学图谱。通过全基因组测序（whole-genome sequencing），我们检测到了单核苷酸变异（SNVs）、插入缺失（indels）、拷贝数畸变以及染色体重排事件。我们利用RNA测序（RNA-Seq）分析了携带突变的基因在对应细胞系中的表达情况，以及不同细胞系间基因表达水平的差异。此外，我们还可检测到已知及新型异常转录本，例如RET融合、ALK融合转录本以及由剪接位点突变引发的转录本异常。类似地，通过靶向捕获亚硫酸氢盐测序（target-captured bisulfite sequencing）与染色质免疫共沉淀测序（ChIP-Seq）分析，我们明确了各细胞系的表观基因组状态及其差异。我们整合上述多组学数据，以阐释观测到的异常基因表达的潜在诱因，尤其是针对典型癌症相关基因的异常表达机制。我们意外发现，不同基因的畸变模式存在显著差异：例如由ChIP-Seq揭示的染色质状态异常是表皮生长因子受体（EGFR）的典型特征，而CDKN2A基因最常见的畸变类型则为大片段基因组缺失与启动子区域高DNA甲基化。本数据集可作为现有临床癌症全外显子组或全基因组测序数据的补充，将为解析各类基因组与表观基因组畸变如何引发癌症中转录组异常表型提供重要研究基础。