The Molecular Taxonomy of Primary Prostate Cancer

Abstract

Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, FLI1) or mutations (SPOP, FOXA1, IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1-mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

“…However, an increased number of circulating L-EVs does not necessarily correspond to an increased DNA content, because perhaps not all L-EVs contain DNA. Furthermore, factors such as genomic instability [47,48], rather than EV number, might have a bigger impact on the amount of DNA in circulating EVs. Highly unstable tumour genomes would provide extrachromosomal DNA, which can then be loaded into L-EVs, ultimately resulting in a subpopulation highly enriched in DNA.…”

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

“…To assess whether IDH1 expression is associated with SREBP activation in human cancers, we analyzed publicly available gene expression data from six different cancer lineages (breast, prostate, colorectal, hepatocellular, lung, and melanoma) through The Cancer Genome Atlas (TCGA) (32)(33)(34)(35)(36). For these analyses, we used an SREBP gene signature based on five well-established SREBP1/2 gene targets (ACACA, FASN, HMGCR, HMGCS1, and LDLR).…”

“…TCGA gene expression data from the breast carcinoma (n ϭ 1,100), prostate adenocarcinoma (n ϭ 498), colorectal adenocarcinoma (n ϭ 382), hepatocellular carcinoma (n ϭ 373), lung adenocarcinoma (n ϭ 517), cutaneous melanoma (n ϭ 471), and lowergrade glioma (n ϭ 530) data sets were downloaded from cBioPortal (29)(30)(31)(32)(33)(34)(35)(36). Mutation data from TCGA was used to identify samples in the lower grade glioma data set with oncogenic mutations in IDH1 (n ϭ 221).…”

Promoter methylation of the immune checkpoint receptor PD-1 (PDCD1) is an independent prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy

“…The AR activity scores were obtained from TCGA Research Network (2015), 10 who assessed the AR output of tumors by calculating an AR activity score from the expression pattern of 20 genes that are experimentally validated AR transcriptional targets. 26 …”