Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Genome Med. 2022 May 17;14(1):50. doi: 10.1186/s13073-022-01055-5.
Hepatocellular carcinoma (HCC) is a common primary liver cancer with poor overall survival. We hypothesized that there are HCC-associated cell-types that impact patient survival.
We combined liver single nucleus (snRNA-seq), single cell (scRNA-seq), and bulk RNA-sequencing (RNA-seq) data to search for cell-type differences in HCC. To first identify cell-types in HCC, adjacent non-tumor tissue, and normal liver, we integrated single-cell level data from a healthy liver cohort (n = 9 non-HCC samples) collected in the Strasbourg University Hospital; an HCC cohort (n = 1 non-HCC, n = 14 HCC-tumor, and n = 14 adjacent non-tumor samples) collected in the Singapore General Hospital and National University; and another HCC cohort (n = 3 HCC-tumor and n = 3 adjacent non-tumor samples) collected in the Dumont-UCLA Liver Cancer Center. We then leveraged these single cell level data to decompose the cell-types in liver bulk RNA-seq data from HCC patients' tumor (n = 361) and adjacent non-tumor tissue (n = 49) from the Cancer Genome Atlas (TCGA) multi-center cohort. For replication, we decomposed 221 HCC and 209 adjacent non-tumor liver microarray samples from the Liver Cancer Institute (LCI) cohort collected by the Liver Cancer Institute and Zhongshan Hospital of Fudan University.
We discovered a tumor-associated proliferative cell-type, Prol (80.4% tumor cells), enriched for cell cycle and mitosis genes. In the liver bulk tissue from the TCGA cohort, the proportion of the Prol cell-type is significantly increased in HCC and associates with a worse overall survival. Independently from our decomposition analysis, we reciprocally show that Prol nuclei/cells significantly over-express both tumor-elevated and survival-decreasing genes obtained from the bulk tissue. Our replication analysis in the LCI cohort confirmed that an increased estimated proportion of the Prol cell-type in HCC is a significant marker for a shorter overall survival. Finally, we show that somatic mutations in the tumor suppressor genes TP53 and RB1 are linked to an increase of the Prol cell-type in HCC.
By integrating liver single cell, single nucleus, and bulk expression data from multiple cohorts we identified a proliferating cell-type (Prol) enriched in HCC tumors, associated with a decreased overall survival, and linked to TP53 and RB1 somatic mutations.
肝细胞癌（HCC）是一种常见的原发性肝癌，整体生存率较差。我们假设存在与 HCC 相关的细胞类型，会影响患者的生存。
我们结合了肝脏单细胞（snRNA-seq）、单细胞（scRNA-seq）和批量 RNA-seq 数据，以寻找 HCC 中的细胞类型差异。为了首先鉴定 HCC、相邻非肿瘤组织和正常肝脏中的细胞类型，我们整合了来自斯特拉斯堡大学医院健康肝脏队列的单细胞水平数据（n=9 例非 HCC 样本）；来自新加坡综合医院和国立大学的 HCC 队列（n=1 例非 HCC、n=14 例 HCC 肿瘤、n=14 例相邻非肿瘤样本）；以及来自 Dumont-UCLA 肝癌中心的另一个 HCC 队列（n=3 例 HCC 肿瘤和 n=3 例相邻非肿瘤样本）。然后，我们利用这些单细胞水平数据来分解来自癌症基因组图谱（TCGA）多中心队列中 HCC 患者肿瘤（n=361）和相邻非肿瘤组织（n=49）的肝脏批量 RNA-seq 数据中的细胞类型。为了复制，我们分解了来自肝癌研究所（LCI）队列的 221 例 HCC 和 209 例相邻非肿瘤肝脏微阵列样本，该队列由肝癌研究所和复旦大学中山医院收集。
我们发现了一种与肿瘤相关的增殖性细胞类型 Prol（80.4%的肿瘤细胞），富含细胞周期和有丝分裂基因。在 TCGA 队列的肝脏批量组织中，Prol 细胞类型的比例在 HCC 中显著增加，并与整体生存率降低相关。独立于我们的分解分析，我们还反过来表明，从批量组织中获得的肿瘤升高和生存降低基因在 Prol 核/细胞中显著过表达。我们在 LCI 队列中的复制分析证实，HCC 中 Prol 细胞类型的估计比例增加是整体生存率较短的显著标志物。最后，我们表明肿瘤抑制基因 TP53 和 RB1 的体细胞突变与 HCC 中 Prol 细胞类型的增加有关。
通过整合来自多个队列的肝脏单细胞、单细胞核和批量表达数据，我们鉴定出一种富含 HCC 肿瘤的增殖性细胞类型（Prol），与整体生存率降低相关，并与 TP53 和 RB1 体细胞突变有关。
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