The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

PMID: 22722839 · DOI: 10.1038/nature11125 · Journal: Nature (2012)

TL;DR

This study sequenced the exomes of 50 lethal, heavily pretreated metastatic castration-resistant prostate cancers (CRPCs) from rapid autopsies and 11 treatment-naive high-grade localized prostate cancers, revealing a low overall mutation rate (2.00/Mb) and identifying novel recurrent mutations in chromatin/histone modifying genes (KMT2D mutated in 8.6%), the AR collaborating factor FOXA1 (3.4%), and CHD1 deletions defining an ETS fusion-negative subtype. The study demonstrated that multiple chromatin remodelers physically interact with AR and are required for AR-mediated signaling.

Cohort & data

• 50 lethal metastatic CRPCs obtained at rapid autopsy (heavily pretreated), including 3 foci from the same patient
• 11 treatment-naive, high-grade localized prostate cancers
• Additional screening cohort: 101 localized and 46 CRPCs for FOXA1 (total n=147)
• Validation across 13 DNA and RNA-based studies totaling 954 prostate cancers (for CHD1 analysis)
• Cancer type: prostate adenocarcinoma (PRAD)
• Dataset: prad_mich
• Method: whole-exome-seq, array CGH, gene expression profiling, transcriptome sequencing

Key findings

• Overall mutation rate in heavily treated CRPC is low at 2.00/Mb, confirming monoclonal origin of lethal CRPC.
• Nine significantly mutated genes identified (FDR ≤ 0.10): TP53, AR, ZFHX3, RB1, PTEN, APC, KMT2D (MLL2), OR5L1, and CDK12.
• CHD1 focal deletion/mutation found in 8% (10/119) of prostate cancers, significantly associated with ETS fusion-negative status (p=0.02, Fisher’s exact test). Across 13 studies, 50/954 (5.2%) prostate cancers were CHD1-negative, 96% of which were ETS-negative (p<0.0001).
• FOXA1 mutated in 5/147 (3.4%) prostate cancers; mutations cluster in C-terminal transactivation domain, repress AR transcriptional program, and increase tumor growth in xenografts (p<0.05).
• KMT2D (MLL2) mutated in 8.6% of prostate cancers; MLL complex members physically interact with AR.
• ETS2 identified as a potential tumor suppressor, deleted in ~1/3 of CRPCs through TMPRSS2:ERG fusions; R437C mutation promotes migration and invasion.
• Multiple chromatin/histone modifying genes mutated including KDM6A (UTX), ASXL1, KMT2A (MLL), ASH2L.
• siRNA knockdown of KMT2A or ASH2L inhibited AR signaling >7.5-fold (each p<0.001), demonstrating functional requirement of MLL complex for AR-mediated transcription.

Genes & alterations

Gene	Alteration	Finding
TP53	Mutations	Significantly mutated in CRPC
AR	Mutations, amplification	Significantly mutated; central to CRPC biology
PTEN	Loss, mutations	Significantly mutated; interaction network identified
RB1	Mutations	Significantly mutated in CRPC
CHD1	Focal deletions, mutations	8% of prostate cancers; defines ETS-negative subtype
FOXA1	Frameshift mutations (S453fs, 340fs, P358fs)	3.4% of prostate cancers; represses AR program, increases tumor growth
KMT2D	Mutations	8.6% of prostate cancers; interacts with AR
CDK12	Mutations	Significantly mutated; novel in prostate cancer
ERG	TMPRSS2:ERG fusion	Most common ETS fusion in prostate cancer
TMPRSS2	Gene fusion partner	Fused to ERG in majority of ETS+ cases
ETS2	R437C mutation, deletion	Tumor suppressor; deleted in ~1/3 CRPCs
ETV3	P327fs, W38*	Deleterious mutations in 2 CRPCs
KDM6A	Mutations	Chromatin modifier interacting with AR
ASXL1	Mutations	Chromatin modifier interacting with AR
ZFHX3	Mutations	Significantly mutated in CRPC
APC	Mutations	Significantly mutated; WNT pathway
PRKDC	I1137fs, E640*	DNA damage response; in aggressive localized case
EZH2	Overexpression	H3K27 methyltransferase overexpressed in CRPC

Clinical implications

• CHD1 loss defines a molecular subtype of ETS fusion-negative prostate cancer, potentially enabling subtype-specific therapeutic strategies.
• FOXA1 mutations promote castration-resistant growth, suggesting FOXA1-mutant tumors may have distinct therapeutic vulnerabilities.
• The MLL complex requirement for AR signaling identifies chromatin modifiers as potential therapeutic targets in CRPC.
• The low mutation rate in heavily treated CRPC suggests genomic complexity arises primarily from copy number alterations and rearrangements rather than point mutations.

Limitations & open questions

• Rapid autopsy specimens represent end-stage disease after extensive treatment; mutations may reflect treatment selection rather than primary drivers.
• Functional validation limited to FOXA1 and ETS2; other novel candidates (CDK12, OR5L1) not functionally characterized.
• Small sample size for localized prostate cancers (n=11) limits statistical power for comparison with CRPC.
• Copy number and expression data from GEO (GSE35988) complement exome data but are from partially overlapping cohorts (31/35 CRPCs sequenced).

Citations from this paper used in the wiki

• “we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy […] and 11 treatment naïve, high-grade localized prostate cancers”
• “We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC”
• “we identified focal deletion/mutation of CHD1 (CHD1−) in 10/119 (8%) prostate cancers, which was significantly associated with ETS gene fusion negative (ETS−) status (two sided Fisher’s exact test, p=0.02)”
• “we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers)”
• “mutated FOXA1 represses androgen signaling and increases tumour growth”
• “we identified somatic mutations of FOXA1 in 4 localized prostate cancers and 1 CRPC (total 5 of 147, 3.4%)”

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