A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

Our plain-English summary of A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma, by C. Liu, Z. Wu, L. Wang, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: C. Liu, Z. Wu, L. Wang, Q. Yang, J. Huang, J. Huang
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(20)
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Globally, hepatocellular carcinoma (HCC) is the sixth most common cancer. In this study, the correlation between mitophagy and HCC prognosis was evaluated using data from The Cancer Genome Atlas (TCGA). Clinical and transcriptomic data of HCC patients were downloaded from TCGA dataset, and mitophagy-related gene (MRG) datasets were obtained from the Molecular Signature Database. Then, a consensus clustering analysis was performed to classify the patients into two clusters. Furthermore, tumor prognosis, clinicopathological features, functional analysis, immune infiltration, immune checkpoint (IC)-related gene expression level, tumor stem cells, ferroptosis status, and N6-methyladenosine analysis were compared between the two clusters. Finally, a mitophagy-related signature was developed. Two clusters (C1 and C2) were identified using the consensus clustering analysis based on the MRG signature. Patients with the C1 subtype exhibited upregulated pathways with better liver function, downregulated cancer-related pathways, lower cancer stem cell scores, lower Tumor Immune Dysfunction and Exclusion scores (TIDE), different ferroptosis status, and better prognosis compared with the patients with the C2 subtype. The C2 subtype was characterized by the increased grade of HCC, as well as the increased number of immune-related pathways and m6A-related genes. Higher immune scores were also observed for the C2 subtype. A signature containing four MRGs (PGAM5, SQSTM1, ATG9A, and GABARAPL1) which can accurately predict the prognosis of HCC patients was then identified. This four-gene signature exhibited a predictive effect in five other cancer types, namely glioma, uveal melanoma, acute myeloid leukemia, adrenocortical carcinoma, and mesothelioma. The mitophagy-associated subtypes of HCC were closely related to the immune microenvironment, immune checkpoint-related gene expression, cancer stem cells, ferroptosis status, m6A, prognosis, and HCC progression. The established MRG signature could predict prognosis in patients with HCC.

In plain English

This was a computer analysis of public genetic data. It did not study asbestos exposure. The authors used tumor gene-activity and clinical data on 371 liver cancer (hepatocellular carcinoma) patients from The Cancer Genome Atlas. They found 21 genes tied both to mitophagy (the cell's clearing of damaged mitochondria) and to survival, and used them to sort patients into two groups. Group C1 survived longer than group C2 (hazard ratio 0.443, 95% confidence interval 0.313 to 0.627). Group C2 had higher cancer stem cell scores and higher TIDE scores, a measure of tumor immune escape. The authors then built a risk score from four genes: PGAM5, SQSTM1, ATG9A and GABARAPL1. The authors used areas under ROC curves (AUCs) to assess the score's sensitivity and specificity. These were 0.772, 0.658 and 0.716 for 1-, 3- and 7-year survival. Versions of the score also predicted survival in five other cancer datasets. In mesothelioma, a version using only PGAM5 and ATG9A gave AUCs of 0.663, 0.772 and 0.693 at 1, 3 and 5 years. The authors concluded the signature could help predict liver cancer survival 'to a certain extent'. They said the genes' roles need laboratory study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatic analysis of publicly available tumor gene-expression (RNA-sequencing) and clinical data; no laboratory or patient-contact work
• Who was studied: 371 hepatocellular carcinoma patients in The Cancer Genome Atlas (TCGA) dataset; other TCGA cancer cohorts, including mesothelioma, were used for the pan-cancer check (their sizes are not given in the text)
• Exposure: No asbestos or fiber exposure was studied. The factor examined was tumor expression of 21 mitophagy-related genes that were also linked to survival.
• Main results:
  • Liver cancer patients in cluster C1 had longer overall survival than those in cluster C2 (HR 0.443, 95% CI 0.313 to 0.627, p = 4.39 times 10 to the power of minus 6)
  • C2 liver cancer patients had higher TIDE scores than C1 patients
  • C2 liver cancer patients had higher cancer stem cell scores
  • In the liver cancer cohort, the low-risk group by the four-gene score had better overall survival than the high-risk group (p = 0.000575)
  • In the liver cancer cohort, the four-gene score's area under the ROC curve for 1-, 3- and 7-year overall survival was 0.772, 0.658 and 0.716; the authors used the ROC analysis to assess sensitivity and specificity
  • The four-gene signature showed a predictive effect in five other TCGA cancer types: glioma, uveal melanoma, acute myeloid leukemia, adrenocortical carcinoma and mesothelioma
  • For the mesothelioma TCGA cohort, the risk score used only two of the four genes, PGAM5 and ATG9A
  • In the mesothelioma TCGA cohort, the low-risk group had better overall survival than the high-risk group (p = 0.000291)
  • In the mesothelioma TCGA cohort, the area under the ROC curve for 1-, 3- and 5-year overall survival was 0.663, 0.772 and 0.693
• The authors' conclusion: The authors concluded that mitophagy was closely related to the immune microenvironment, immune checkpoint genes, cancer stem cells and prognosis in liver cancer patients. They said the gene signature would be an effective strategy for liver cancer management 'to a certain extent'.
• Limitations the authors state:
  • The specific role of the mitophagy-related genes in liver cancer still needs to be shown in laboratory (in vitro) and animal (in vivo) studies
  • How mitophagy genes act in liver cancer progression needs further study

Topics

Medical terms in this study, explained in our Lexicon: Prognosis, Carcinoma, STEM, Mesothelioma.

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