The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer

By Catherine S. Grasso, Yi-Mi Wu, D. Robinson, Xuhong Cao, S. Dhanasekaran, Amjad P. Khan, M. Quist, Xiaojun Jing, R. Lonigro, J. Brenner and 17 more. Nature, 2012

2,459 citations recorded by the source corpus.

Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a2f4ae17c0c6c1515d2915e9513a76048e87962b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Pulmonary and Respiratory Medicine

Citations in the corpus

Comprehensive molecular portraits of invasive lobular breast cancer (2015, methodology): “A similar mutational pattern was observed by combining multiple prostate cancer sequencing studies (Baca et al., 2013; Barbieri et al., 2012; Grasso et al., 2012; Robinson et al., 2015) (Figure S3A), and confirmed by the TCGA prostate cancer project (Robinson et al., 2015).”
Punctuated Evolution of Prostate Cancer Genomes (2013, neutral): “localized and castration-resistant prostate cancer has identified base-pair mutations in genes such as SPOP, FOXA1, and KDM6A, which implicate a range of deregulated cellular processes in prostate tumor development (Barbieri et al., 2012; Grasso et al., 2012; Kumar et al., 2011).”
Organoid cultures derived from patients with advanced prostate cancer (2014, positive): “TP53, the most commonly mutated gene in CRPC (Grasso et al., 2012; Kumar et al., 2011), was mutant in four organoid samples (Figure 2C).”
Identification of multipotent luminal progenitor cells in human prostate organoid cultures (2014, background): “Several large-scale prostate cancer genome resequencing studies have nowdefined a plethora of novel genomic alterations in primary and metastatic cancer whose functions are currently unknown (Barbieri et al., 2012; Grasso et al., 2012; Taylor et al., 2010).”
Genetics and biology of prostate cancer (2018, methodology): “Primary prostate tumors and mCRPC exhibit markedly increased genome-wide copy number alterations yet show only modestly increased mutations (Taylor et al. 2010; Grasso et al. 2012; Hieronymus and Sawyers 2012; The Cancer Genome Atlas Research Network 2015).”
Integrative clinical genomics of advanced prostate cancer (2015, positive): “, 1995) and in the androgen signaling pathway (Beltran et al., 2013; Grasso et al., 2012; Gundem et al., 2015; Hong et al., 2015), although these studies were performed predominantly using autopsy samples or preclinical models with limited cohort sizes.”