Abstract
Background
Anoikis is a cell death programmed to eliminate dysfunctional or damaged cells induced by detachment from the extracellular matrix. Utilizing an anoikis-based risk stratification is anticipated to understand melanoma's prognostic and immune landscapes comprehensively.
Methods
Differential expression genes (DEGs) were analyzed between melanoma and normal skin tissues in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data sets. Next, least absolute shrinkage and selection operator, support vector machine–recursive feature elimination algorithm, and univariate and multivariate Cox analyses on the 308 DEGs were performed to build the prognostic signature in the TCGA–melanoma data set. Finally, the signature was validated in GSE65904 and GSE22155 data sets. NOTCH3, PIK3R2, and SOD2 were validated in our clinical samples by immunohistochemistry.
Results
The prognostic model for melanoma patients was developed utilizing ten hub anoikis-related genes. The overall survival (OS) of patients in the high-risk subgroup, which was classified by the optimal cutoff value, was remarkably shorter in the TCGA–melanoma, GSE65904, and GSE22155 data sets. Low-risk patients exhibited low immune cell infiltration and high expression of immunophenoscores and immune checkpoints. They also demonstrated increased sensitivity to various drugs, including dasatinib and dabrafenib. NOTCH3, PIK3R2, and SOD2 were notably associated with OS by univariate Cox analysis in the GSE65904 data set. The clinical melanoma samples showed remarkably higher protein expressions of NOTCH3 (P = 0.003) and PIK3R2 (P = 0.009) than the para-melanoma samples, while the SOD2 protein expression remained unchanged.
Conclusions
In this study, we successfully established a prognostic anoikis-connected signature using machine learning. This model may aid in evaluating patient prognosis, clinical characteristics, and immune treatment modalities for melanoma.
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Data availability
This study's data generated or examined are comprehensively presented in this article or the supplementary materials. Without reservation, the author is committed to providing the raw data confirming the outcomes of this article to qualified researchers.
Abbreviations
- ML:
-
Machine learning
- GTEx:
-
Genotype-tissue expression
- TCGA:
-
The cancer genome atlas
- SVM–RFE:
-
Support vector machine–recursive feature elimination
- ICPs:
-
Immune checkpoints
- IPSs:
-
Immunophenoscores
- LASSO:
-
Least absolute shrinkage and selection operator
- DEGs:
-
Differentially expressed genes
- DAVID:
-
Database for annotation, visualization and integrated discovery
- TSG101:
-
Tumor susceptibility gene 101
- NQO1:
-
NAD(P)H dehydrogenase (quinone 1)
- EGFR:
-
Epidermal growth factor receptor
- DAPK2:
-
Death-associated protein kinase 2
- CEBPB:
-
CCAAT enhancer binding protein b
- BNIP3:
-
Bcl-2/E1B 19 kDa interacting protein
- ANXA5:
-
Annexin A5
- PIK3R2:
-
Phosphatidylinositol 3-kinase p85beta
- SOD2:
-
Superoxide dismutase 2
- GO:
-
Gene Ontology
- KEGG:
-
Kyoto encyclopedia of genes and genomes
- AUC:
-
Area under the curve
- AJCC:
-
American Joint Committee on Cancer
- ROC:
-
Receiver operating characteristic
- GDSC:
-
Genomics of drug sensitivity in cancer
- IHC:
-
Immunohistochemistry
- HR:
-
Hazard regression
- TME:
-
Tumor microenvironment
- IPSs:
-
Immunophenoscores
- ICPs:
-
Immune checkpoints
- CAF:
-
Cancer-associated fibroblast
- MDSC:
-
Myeloid derived suppressive cell
- M2 TAM:
-
M2 tumor-associated macrophages
- PD-1:
-
Anti-programmed death 1
- CTLA-4:
-
Anti-cytotoxic T lymphocyte-associated antigen 4
- PD-L1:
-
Programmed death ligand 1
- TIM3:
-
Mucin-domain containing-3
- LAG3:
-
Lymphocyte-activation gene-3
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This research was supported by the National Science Foundation of China [grant number 31870974].
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Conceptualization, JL; data curation, JL, NN and RM; formal analysis, JL and SZ; funding acquisition, GL and YL; investigation, JL; methodology, JL and QD; software, JL; supervision, GL; validation, JL and SC; visualization, JL; writing—original draft, JL and GL; writing—review and editing, GL and YL.
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12094_2023_3336_MOESM1_ESM.docx
Supplementary data to this article can be found online. Supplementary Table S1. The coefficients assessed by multivariate Cox regression. Supplementary Table S2. Correlations between the expression of NOTCH3 and PIK3R2 and clinical characteristics in melanoma patients. Supplementary Figure S1. Univariate Cox regression, OS, and ROC analysis of melanoma patients in the GSE65904 or GSE22155 datasets. (A)OS analysis of melanoma patients in the GSE22155 dataset. (B)ROC analysis of melanoma patients in the GSE22155 dataset. (C)Univariate Cox regression of melanoma patients in the GSE65904 dataset. (DOCX 266 KB)
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Liu, J., Ma, R., Chen, S. et al. Anoikis patterns via machine learning strategy and experimental verification exhibit distinct prognostic and immune landscapes in melanoma. Clin Transl Oncol 26, 1170–1186 (2024). https://doi.org/10.1007/s12094-023-03336-w
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DOI: https://doi.org/10.1007/s12094-023-03336-w