This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research article
Gang Ning
Guangzhou First People's Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5554-5735
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed expression profiles and prognostic values of 13 widely reported m6A modification related genes in HCC.
Methods: mRNA expression of 13 m6A modification related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211 and GSE78220. Univariate and LASSO analysis was used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature.
Results: FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1 and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high risk patients with shorter OS and DFS and low risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils and Tregs were found to be enriched in HCC patients with high risk score, while significantly higher proportions of memory CD4 T cells, gamma delta T cells and naive B cells were found to be enriched in HCC patients with high low score. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in non-responders, and anti-PD-1 immunotherapy treated patients with lower risk score had better OS than patients with higher risk score.
Conclusion: A risk signature developed with the expression of 5 m6A related genes could improve the prediction of prognosis of HCC and correlate with sorafenib treatment and anti-PD-1 immunotherapy response.
Keywords
hepatocellular carcinoma, N6-methyladenosine (m6A), risk signature, tumor-infiltrating immune cells, sorafenib, anti-PD-1 immunotherapy
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This is a list of supplementary files associated with this preprint. Click to download.
- Supplementaryfigure1.tif
Supplementary figure 1: Association of m6A modification related genes with OS of HCC patients. Univariate analysis of mRNA expression of m6A modification related genes with OS of HCC patients (A). Multivariate analysis of mRNA expression of m6A modification related genes with OS of HCC patients (B-J). Gender: male vs female; age: >60 vs≤60; grade: G3+G4 vs G1+G2; T: T1 vs T0; N: N1vs N0; M: M1 vs M0; TNM stage: stage III+IV vs stage I+II.
- Supplementaryfigure2.tif
Supplementary figure 2: Relationship of m6A modification related genes with DFS of HCC patients. Univariate analysis of mRNA expression of m6A modification related genes with DFS of HCC patients (A). Multivariate analysis of mRNA expression of m6A modification related genes with DFS of HCC patients (B-H). Gender: male vs female; age: >60 vs≤60; grade: G3+G4 vs G1+G2; T: T1 vs T0; N: N1vs N0; M: M1 vs M0; TNM stage: stage III+IV vs stage I+II.
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research article
Gang Ning
Guangzhou First People's Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5554-5735
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 21 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed expression profiles and prognostic values of 13 widely reported m6A modification related genes in HCC.
Methods: mRNA expression of 13 m6A modification related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211 and GSE78220. Univariate and LASSO analysis was used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature.
Results: FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1 and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high risk patients with shorter OS and DFS and low risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils and Tregs were found to be enriched in HCC patients with high risk score, while significantly higher proportions of memory CD4 T cells, gamma delta T cells and naive B cells were found to be enriched in HCC patients with high low score. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in non-responders, and anti-PD-1 immunotherapy treated patients with lower risk score had better OS than patients with higher risk score.
Conclusion: A risk signature developed with the expression of 5 m6A related genes could improve the prediction of prognosis of HCC and correlate with sorafenib treatment and anti-PD-1 immunotherapy response.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
This is a list of supplementary files associated with this preprint. Click to download.
- Supplementaryfigure1.tif
Supplementary figure 1: Association of m6A modification related genes with OS of HCC patients. Univariate analysis of mRNA expression of m6A modification related genes with OS of HCC patients (A). Multivariate analysis of mRNA expression of m6A modification related genes with OS of HCC patients (B-J). Gender: male vs female; age: >60 vs≤60; grade: G3+G4 vs G1+G2; T: T1 vs T0; N: N1vs N0; M: M1 vs M0; TNM stage: stage III+IV vs stage I+II.
- Supplementaryfigure2.tif
Supplementary figure 2: Relationship of m6A modification related genes with DFS of HCC patients. Univariate analysis of mRNA expression of m6A modification related genes with DFS of HCC patients (A). Multivariate analysis of mRNA expression of m6A modification related genes with DFS of HCC patients (B-H). Gender: male vs female; age: >60 vs≤60; grade: G3+G4 vs G1+G2; T: T1 vs T0; N: N1vs N0; M: M1 vs M0; TNM stage: stage III+IV vs stage I+II.
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