Skip to main content
Premium Trial:

Request an Annual Quote

Structural Changes Affecting Androgen Receptor Locus, Enhancer May Fuel Metastatic Prostate Cancer

NEW YORK (GenomeWeb) – Structural alterations appear to drive castration-resistant prostate cancer, a study using linked-read genome sequencing has found.

Using 10X Genomics' linked-read genome sequencing approach, researchers from the Dana-Farber Cancer Institute and elsewhere analyzed 23 metastatic castration-resistant prostate cancer biopsies as well as cell-free DNA from 86 additional patients with metastatic disease. In the US, there are about 29,430 deaths a year due to prostate cancer, mostly of people with metastatic disease, according to the National Cancer Institute.

As they reported in Cell today, the researchers uncovered a number of rearrangements among the metastatic castration-resistant prostate cancer samples, including ones affecting the androgen receptor (AR) locus and an AR enhancer.

"Our findings highlight the complex genomic structure of [metastatic castration-resistant prostate cancer] mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered," Dana-Farber's Matthew Meyerson and his colleagues wrote.

They performed long-range, linked-read whole genome sequencing using the 10XG approach on 23 metastatic biopsy specimens and matched germline controls. The 10XG approach generates barcoded short-read libraries from high-molecular weight fragments and, in this study, the researchers said it would enable them to better detect structural variations.

Eleven samples came from patients before they began treatment and 12 were from patients who had progressed on either an androgen synthesis inhibitor or AR pathway antagonist. Three samples were from the same patients before and after they progressed.

Using read alignments, local assembly and barcodes and three different detection methods, they identified about 230 structural variants per sample. Because of their small sample size, the researchers restricted their analysis to genes already implicated in prostate cancer.

Once inactivating rearrangements were considered, 19 of the 23 cases they analyzed had biallelic inactivation of tumor-suppressing genes. This, the researchers said, underscores the importance of rearrangements in altering known prostate cancer genes.

Five samples from four different patients harbored an increased number of tandem duplication as compared to other types of SVs. Four of these five tandem duplicator phenotype samples had biallelic inactivation of CDK12, the researchers noted. They also reported that the tandem duplicator phenotype could be detected through ultra-low pass whole-genome sequencing of cell-free DNA from patients with metastatic disease.

In an additional cohort of 285 samples from mCRPC patients who'd undergone whole-exome sequencing, they also noted that the tandem duplicator phenotype samples were enriched for CDK12 alterations and found that the alterations appeared to be clonal. This indicates that CDK12 inactivation and the tandem duplicator phenotype are early events, the researchers said.

Meyerson and his colleagues also found that a number of the structural alterations affected Myc or AR, often leading to their duplication. There is typically sustained AR signaling in this disease phase, they noted.

They added, though, that the peak region of copy number changes near the AR gene actually falls upstream of the gene body and overlaps with regions thought to act as AR enhancers. For all 16 samples in their cohort with copy-number gains affecting AR, the upstream enhancer region was also included, the researchers reported. That, they added, was also the case in 70 percent of the cell-free DNA samples.

Further evidence from a recently reported mCRPC cohort with paired exome and transcriptome sequencing supports the idea that AR gene and AR enhancer gain drives an increase in AR expression in the castration-resistant phase of prostate cancer, the researchers said.

Meyerson and his colleagues also examined DNA samples collected from patients before and during their treatment with a next-generation AR pathway inhibitor to find consistent selective pressure on the AR locus. They noted that enhancer gain occurred in all 12 post-progression samples in their cohort.

"A picture emerges of complex and diverse genetic alterations converging on a central need to sustain AR signaling in the face of highly potent androgen pathway blockade in mCRPC," they said.