Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing

Abstract

SUMMARY Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC) but there have been few whole genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these include highly recurrent tandem duplications involving an upstream enhancer of AR in 70-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the noncoding mCRPC genome remain to be discovered.

The genomic landscape of metastatic castration-resistant prostate cancers using whole genome sequencing reveals multiple distinct genotypes with potential clinical impact

“…In an additional 6.6% and 14.7% of tumors only AR gene alterations or AR -enhancer amplification occurred, respectively. The percentage of mCRPC patients with the exclusive AR -enhancer amplification (29 out of 197; 14.7%) versus exclusively AR -locus amplification (13 out of 197; 6.6%) is similar to previous observations which showed 21 out of 94 CRPC patients (10.3%) with exclusively AR -enhancer amplification versus 4 out of 94 CRPC patients (4.3%) with exclusively AR -locus amplification 20 . Thus, concurrent amplification of the AR gene and the AR -enhancer was not necessarily of equal magnitude, which resulted in differences in copy number enrichment of these loci (Figure 4b).…”

“…The use of WGS also allowed us to gain more insight into the role of non-coding regions of the genome in prostate cancer. We confirmed the amplification of a recently reported AR -enhancer 20,21,30 . In line with the cell line-based observations, we show AR binding at these mCRPC-specific enhancer regions, providing the first clinical indication that AR -enhancer amplification also increases AR signaling in mCRPC tumors.…”

“…Focusing on the AR-pathway revealed that aberrant AR signaling occurred in 80% of our patients. In 57.3% of patients both AR and the AR -enhancer (~66.13 Mb on chromosome X; located about 629 kbp upstream of the AR gene 20 ) were affected (Figure 4a). In an additional 6.6% and 14.7% of tumors only AR gene alterations or AR -enhancer amplification occurred, respectively.…”

Pan-cancer whole genome analyses of metastatic solid tumors

“…In tumor types with high rates of amplifications, these amplifications are generally found across a broad spectrum of oncogenes, suggesting there are mutagenic processes active in these tissues that favor amplifications, rather than tissue-specific selection of individual driver genes. AR and EGFR are notable exceptions, with highly selective amplifications in prostate, and in CNS and lung cancers, respectively, in line with previous reports 20,40,41 . Intriguingly, we also found two-fold more amplification drivers in samples with WGD despite amplifications being defined as relative to the average sample ploidy.…”

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

“…2,3 Comparison of genomic landscapes from primary and metastatic tumor samples shows that resistance mechanisms are centered on androgen signaling and include overexpression, rearrangement of the gene locus, enhancer hijacking, ligand-binding domain (LBD) mutations and aberrant splice variants of the AR. [4][5][6][7][8] In addition, increased androgen synthesis linked to overexpression of steroidogenesis enzymes in tumor tissue is observed. 9 These findings vindicate ongoing efforts toward the identification of more efficacious AR signaling blockers.…”