Journal
GENOME MEDICINE
Volume 14, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13073-022-01055-5
Keywords
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Categories
Funding
- HHMI Gilliam Fellowship
- American Association of the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology grant
- CURE: Digestive Diseases Research Center [DKP304131]
- NCI Translational Liver Cancer (TLC) Consortium [U01 CA230997-1]
- NIH/NCI [R21 CA216807, R01 CA246304]
- NIH Cancer Center Support Grant [P30CA016042-45]
- NIH [R01HG006139, R01HG009120, R35GM141798, R01HG010505]
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In this study, 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, by integrating data from multiple cohorts.
Background 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. Methods 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. Results 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. Conclusions 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.
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