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Molecular classification and subtype-specific drug sensitivity research of uterine carcinosarcoma under multi-omics
Xiaofan Lu1, Liya Zhang1, Huiling Zhao1
1a Research Center of Biostatistics and Computational Pharmacy , China Pharmaceutical University , Nanjing , P.R.China.
Objective:
Uterine carcinosarcomas (UCSs) are aggressive rare tumors recognized as malignancies composed of metaplastic transformation of epithelial elements. Nay no comprehensive molecular classification has been applied to UCS to guide targeted therapies so far, which motivated us to subtyping UCS by aggregating multiple genomic platform data.
Methods:
We classified UCS into three distinct subtypes with different clinicopathologic and molecular characterization by using similarity network fusion under consensus clustering framework (SNFCC+) to aggregate four genomic data platforms of 55 UCS patients. Differences across subtypes were extracted by functional enrichment, gene mutations and clinical features. Subtypes were further distinguished by putative biomarkers. We also determined associations between individual oncogenes and chemotherapeutics to discuss subtype-specific drug sensitivity.
Results:
Functional enrichment analysis of the subtype-specific differential expression genes endowed three subtypes new designation: Myo, Cell and Hormone. Mutations in PTEN, PIK3CA, ARID1A and PPP2R1A altered across subtypes. The epithelial-to-mesenchymal transition (EMT) score distinguished Myo from another two subtypes whereby a high EMT scores prevalently existed and each case was judged as M (mesenchymal) phenotype in Myo subtype. Through the drug sensitivity analysis, we found that the response to - tinib drugs is quite different across subtypes according to expression level. Additionally, different subtypes' response to broad-spectrum anti-cancer drug paclitaxel may be also different.
Conclusions:
In this study, we identified three distinct molecular subtypes of UCS with different features. Subtypes were also revealed to have different sensitivity to existing chemotherapy drugs, which may support in-depth study of subtype-specific dosing regimens.
Insights
Uterine carcinosarcomas (UCSs) were classified into three molecular subtypes using genomic data. These subtypes exhibit distinct features and varying sensitivities to chemotherapy, paving the way for personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Uterine carcinosarcomas (UCSs) are aggressive, rare malignancies.
- A comprehensive molecular classification is lacking for UCS, hindering targeted therapy development.
Purpose of the Study:
- To subtype UCS by integrating multiple genomic data platforms.
- To identify distinct molecular subtypes with unique clinicopathologic and molecular characteristics.
- To explore subtype-specific drug sensitivities for targeted therapeutic strategies.
Main Methods:
- Applied similarity network fusion under a consensus clustering framework (SNFCC+) to aggregate data from four genomic platforms for 55 UCS patients.
- Utilized functional enrichment, gene mutation analysis, and clinical features to differentiate subtypes.
- Investigated associations between oncogenes and chemotherapeutics for subtype-specific drug sensitivity.
Main Results:
- Identified three distinct molecular subtypes of UCS: Myo, Cell, and Hormone, characterized by differential gene expression.
- Observed subtype-specific mutations in genes including PTEN, PIK3CA, ARID1A, and PPP2R1A.
- Found varying sensitivities to targeted therapies (e.g., -tinib drugs) and paclitaxel across subtypes, with the Myo subtype exhibiting a mesenchymal (M) phenotype linked to high epithelial-to-mesenchymal transition (EMT) scores.
Conclusions:
- Successfully identified three distinct molecular subtypes of UCS with unique biological features.
- Demonstrated differential drug sensitivity among the identified subtypes, suggesting potential for personalized chemotherapy regimens.
- This molecular subtyping provides a foundation for developing subtype-specific treatment strategies and dosing for UCS.
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