APOBEC family reshapes the immune microenvironment and therapy sensitivity in clear cell renal cell carcinoma.
APOBEC family
Clear cell renal cell carcinoma
Machine learning
Molecular subtypes
Multiomics
Tumor immunity
Journal
Clinical and experimental medicine
ISSN: 1591-9528
Titre abrégé: Clin Exp Med
Pays: Italy
ID NLM: 100973405
Informations de publication
Date de publication:
09 Sep 2024
09 Sep 2024
Historique:
received:
01
07
2024
accepted:
11
08
2024
medline:
9
9
2024
pubmed:
9
9
2024
entrez:
9
9
2024
Statut:
epublish
Résumé
Emerging evidence suggests that the APOBEC family is implicated in multiple cancers and might be utilized as a new target for cancer detection and treatment. However, the dysregulation and clinical implication of the APOBEC family in clear cell renal cell cancer (ccRCC) remain elusive. TCGA multiomics data facilitated a comprehensive exploration of the APOBEC family across cancers, including ccRCC. Remodeling analysis classified ccRCC patients into two distinct subgroups: APOBEC family pattern cancer subtype 1 (APCS1) and subtype 2 (APCS2). The study investigated differences in clinical parameters, tumor immune microenvironment, therapeutic responsiveness, and genomic mutation landscapes between these subtypes. An APOBEC family-related risk model was developed and validated for predicting ccRCC patient prognosis, demonstrating good sensitivity and specificity. Finally, the overview of APOBEC3B function was investigated in multiple cancers and verified in clinical samples. APCS1 and APCS2 demonstrated considerably distinct clinical features and biological processes in ccRCC. APCS1, an aggressive subtype, has advanced clinical stage and a poor prognosis. APCS1 exhibited an oncogenic and metabolically active phenotype. APCS1 also exhibited a greater tumor mutation load and immunocompromised condition, resulting in immunological dysfunction and immune checkpoint treatment resistance. The genomic copy number variation of APCS1, including arm gain and loss, was much more than that of APCS2, which may help explain the tired immune system. Furthermore, the two subtypes have distinct drug sensitivity patterns in clinical specimens and matching cell lines. Finally, we developed a predictive risk model based on subtype biomarkers that performed well for ccRCC patients and validated the clinical impact of APOBEC3B. Aberrant APOBEC family expression patterns might modify the tumor immune microenvironment by increasing the genome mutation frequency, thus inducing an immune-exhausted phenotype. APOBEC family-based molecular subtypes could strengthen the understanding of ccRCC characterization and guide clinical treatment. Targeting APOBEC3B may be regarded as a new therapeutic target for ccRCC.
Identifiants
pubmed: 39249558
doi: 10.1007/s10238-024-01465-2
pii: 10.1007/s10238-024-01465-2
doi:
Substances chimiques
APOBEC Deaminases
EC 3.5.4.5
Minor Histocompatibility Antigens
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
212Subventions
Organisme : The National Natural Science Foundation of China
ID : 81902560,81730073, 81872074
Organisme : The National Natural Science Foundation of China
ID : 81902560,81730073, 81872074
Organisme : The National Natural Science Foundation of China
ID : 81902560,81730073, 81872074
Organisme : The National Natural Science Foundation of China
ID : 81902560,81730073, 81872074
Organisme : The China National Key Research and Development Program Stem Cell and Translational Research Key Projects
ID : 2018YFA0108300
Organisme : The China National Key Research and Development Program Stem Cell and Translational Research Key Projects
ID : 2018YFA0108300
Organisme : The China National Key Research and Development Program Stem Cell and Translational Research Key Projects
ID : 2018YFA0108300
Organisme : The China National Key Research and Development Program Stem Cell and Translational Research Key Projects
ID : 2018YFA0108300
Informations de copyright
© 2024. The Author(s).
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