Cited 3 times since 2022 (2.2 per year) source: EuropePMC Clinical cancer research : an official journal of the American Association for Cancer Research, Volume 28, Issue 24, 1 1 2022, Pages 5396-5404 Intrinsic Molecular Subtypes of Metastatic Castration-Resistant Prostate Cancer. Feng E, Rydzewski NR, Zhang M, Lundberg A, Bootsma M, Helzer KT, Lang JM, Aggarwal R, Small EJ, Quigley DA, Sjöström M, Zhao SG
Purpose
Although numerous biology-driven subtypes have been described previously in metastatic castration-resistant prostate cancer (mCRPC), unsupervised molecular subtyping based on gene expression has been less studied, especially using large cohorts. Thus, we sought to identify the intrinsic molecular subtypes of mCRPC and assess molecular and clinical correlates in the largest combined cohort of mCRPC samples with gene expression data available to date.
Experimental design
We combined and batch-effect corrected gene expression data from four mCRPC cohorts from the Fred Hutchinson Cancer Research Center (N = 157), a small-cell neuroendocrine (NE) prostate cancer (SCNC)-enriched cohort from Weill Cornell Medicine (N = 49), and cohorts from the Stand Up 2 Cancer/Prostate Cancer Foundation East Coast Dream Team (N = 266) and the West Coast Dream Team (N = 162).
Results
Hierarchical clustering of RNA-sequencing data from these 634 mCRPC samples identified two distinct adenocarcinoma subtypes, one of which (adeno-immune) was characterized by higher gene expression of immune pathways, higher CIBERSORTx immune scores, diminished ASI benefit, and non-lymph node metastasis tropism compared with an adeno-classic subtype. We also identified two distinct subtypes with enrichment for an NE phenotype, including an NE-liver subgroup characterized by liver metastasis tropism, PTEN loss, and APC and SPOP mutations compared with an NE-classic subgroup.
Conclusions
Our results emphasize the heterogeneity of mCRPC beyond currently accepted molecular phenotypes, and suggest that future studies should consider incorporating transcriptome-wide profiling to better understand how these differences impact treatment responses and outcomes.
