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Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer

ABSTRACT: Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer

PROVIDER: PRJNA820785 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18506800_1.fastq.gz	Fastqsanger.gz
	SRR18506800_2.fastq.gz	Fastqsanger.gz
	SRR18506900_1.fastq.gz	Fastqsanger.gz
	SRR18506900_2.fastq.gz	Fastqsanger.gz
	SRR18506801_1.fastq.gz	Fastqsanger.gz

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Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer

Project description:Metastatic prostate cancers are recognized to exhibit subtypes categorized by underlying genomic alterations and phenotypes largely partitioned by androgen receptor signaling and neuroendocrine activity. In the present study we evaluated a phenotypic classification approach originally developed for subtyping breast carcinomas using the PAM50 gene signature. PAM50 subtypes associated with specific genotypes such as RB1 loss and phenotypes such as small cell/neuroendocrine carcinoma as well as tumor histology including cribriform morphology. In the context of clinical translation, PAM50 classification segregated tumors into groups with distinct druggable targets such as cell surface proteins amenable to antibody-drug-conjugates (ADCs). Classification into Luminal A, Luminal B and Basal tumors associated with time on androgen receptor signaling inhibitors, and responses to taxane chemotherapy. These findings support further clinical investigation of PAM50-based classification for prostate cancer patient stratification in therapeutic studies.

2022-05-03 | GSE199596 | GEO

Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer.

Project description:PurposeTo determine whether metastatic castration-resistant prostate cancers (mCRPC) partition into molecular phenotypes corresponding to intrinsic differentiation states and ascertain whether these subtypes exhibit specific druggable features and associate with treatment outcomes.Experimental designWe used RNAseq, digital spatial profiling, and histological assessments from metastatic biopsies and patient-derived xenografts to segregate mCRPCs into subtypes defined by the PAM50 breast cancer classification algorithm. Subtype associations with treatment responses in preclinical models and patients were determined.ResultsUsing the PAM50 algorithm, we partitioned 270 mCRPC tumors into LumA (42%), LumB (24%), and Basal (34%) subtypes with classification largely driven by proliferation rates and androgen receptor (AR) activity. Most neuroendocrine tumors classified as Basal. Pathways enriched in the LumA subtype include TGFß and NOTCH signaling. LumB subtype tumors were notable for elevated MYC activity. Basal subtype tumors exhibited elevated IL6-STAT3 signaling and features of adult stem cell states. In patients where multiple tumors were evaluated, the majority had concordant PAM50 subtype determination, though a subset exhibited marked inter- and intratumor heterogeneity, including divergent classifications between primary and metastatic sites. In preclinical models, LumA subtype tumors were highly responsive to androgen deprivation and docetaxel chemotherapy whereas Basal tumors were largely resistant. In clinical cohorts patients with Basal subtype tumors demonstrated a shorter time on treatment with AR signaling inhibitors and docetaxel relative to patients with luminal subtypes.ConclusionsSubtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.

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Epigenetic footprint of hepatoblastoma defines a novel integrative molecular classification with clinical implications

Project description:Epigenetic footprint of hepatoblastoma defines a novel integrative molecular classification with clinical implications

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Intra-Tumor DNA Methylation Heterogeneity in Glioblastoma Implications for DNA Methylation-based Classification

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Molecular classification of bladder cancer: global mRNA classification versus tumor cell phenotype classification.

Project description:In this study gene expression profiles for 307 cases of advanced bladder cancers were compared to molecular phenotype at the tumor cell level. TUR-B tissue for RNA extraction was macrodissected from the close vicinity of the tissue sampled for immunohistochemistry to ensure high-quality sampling and to minimize the effects of intra-tumor heterogeneity. Despite excellent agreement between gene expression values and IHC-score at the single marker level, broad differences emerge when samples are clustered at the global mRNA versus tumor cell (IHC) levels. Classification at the different levels give different results in a systematic fashion, which implicates that analysis at both levels is required for optimal subtype-classification of bladder cancer.

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Intrinsic Molecular Subtypes of Metastatic Castration-Resistant Prostate Cancer.

Project description:PurposeAlthough 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 designWe 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).ResultsHierarchical 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.ConclusionsOur 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.

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Epigenetic footprint of hepatoblastoma defines a novel integrative molecular classification with clinical implications [CytoScanHD_Array]

Project description:Epigenetic footprint of hepatoblastoma defines a novel integrative molecular classification with clinical implications [CytoScanHD_Array]

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GATA2 shRNA Expression in Castration Resistant Prostate Cancer Cell Lines

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Whole Transcriptomic Sequencing of Metastatic Castration Resistant Prostate Cancer Samples

Project description:We report the gene expression profile of 8 metastatic castration resisistant prostate cancer samples analyzed by paired-end RNA-seq. We found evidence of extensive abnormal splicing as well as several novel fusion genes. Finally, we also observed several recurrent high-confidence somatic mutations. Paired-end RNA-seq by rRNA depletion

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