Transcriptome subtyping of metastatic Castration Resistance Prostate Cancer (mCRPC) for the precision therapeutics:
Yingchun Liang1,2, Enlin Rong3, Jin Qian4
1Departments of Urology, Huashan Hospital, Fudan University, No. 12 WuLuMuQi Middle Road, 200040, Shanghai, China.
Background:
Men with metastatic prostate cancer who are treated with androgen deprivation therapy (ADT) typically develop therapeutic resistance eventually and have a dismal outcome. Moreover, the limited survival benefit observed in only a proportion of patients receiving novel therapeutics including immune checkpoint blockade and PARP inhibitors suggests the biological heterogeneity of mCRPCs.
Methods:
To understand the heterogeneity of mCRPC, we analyzed the transcriptome of 231 mCRPCs and identified four disparate biological subtypes (Basal, Homologous Recombination Repair (HRR), Neuroendocrine and Luminal). The package "randomForest" was used to construct a Random Forest model. Circular plots were used for visualization of TMPRSS2-ERG fusion in each subtype.
Results:
The Luminal subtype of mCRPCs has higher Androgen Receptor (AR) expression and copy number alterations as compared with the other subtypes. Genes in HRR pathway are relatively downregulated in most subtypes regardless of the genetic alterations, except for the HRR and NE subtypes, suggesting potential resistance of the HRR and NE mCRPCs to PARP inhibitor treatment. The HRR subtype has relatively more immune cell infiltration and higher expression of immune checkpoints, highlighting that the efficacy of immunotherapy should be evaluated in this particular subtype. TMPRSS2-ERG fusion is the most frequent gene fusion in all mCRPCs, and the Basal subtype has a higher frequency of this fusion than the other subtypes.
Conclusions:
Our results reveal that the stratification of mCRPC according to transcriptome is informative of personalized therapeutics in the treatment of mCRPCs. The predictive capacity of the transcriptome subtyping of mCRPC warrants further exploration in the future.
Insights
Metastatic castration-resistant prostate cancer (mCRPC) shows significant biological heterogeneity. Transcriptome analysis identified four subtypes (Basal, HRR, Neuroendocrine, Luminal), informing personalized treatment strategies for mCRPC patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Androgen deprivation therapy (ADT) resistance is common in metastatic castration-resistant prostate cancer (mCRPC), leading to poor outcomes.
- Limited efficacy of novel therapies like immune checkpoint inhibitors and PARP inhibitors suggests underlying biological heterogeneity in mCRPC.
Purpose of the Study:
- To investigate the biological heterogeneity of mCRPC.
- To identify distinct molecular subtypes within mCRPC.
- To correlate molecular subtypes with potential therapeutic vulnerabilities.
Main Methods:
- Transcriptome analysis of 231 mCRPC samples.
- Utilized Random Forest modeling for classification.
- Visualized TMPRSS2-ERG fusion frequency using circular plots.
Main Results:
- Identified four mCRPC subtypes: Basal, Homologous Recombination Repair (HRR), Neuroendocrine (NE), and Luminal.
- Luminal subtype exhibits higher Androgen Receptor (AR) expression and copy number alterations.
- HRR subtype shows increased immune cell infiltration and immune checkpoint expression, suggesting immunotherapy potential.
- Basal subtype has a higher frequency of TMPRSS2-ERG fusion.
Conclusions:
- Transcriptome-based subtyping of mCRPC is informative for personalized therapeutic strategies.
- Further research is warranted to explore the predictive capacity of mCRPC transcriptome subtyping for treatment selection.
