# Genomic hallmarks and structural variation in metastatic prostate cancer

Source: https://onco.cc/key-papers/paper-quigley-structural-variation-mcrpc-cell-2018/  
OnCo record `paper-quigley-structural-variation-mcrpc-cell-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading 101 advanced prostate cancers by whole genome rather than by gene panel found that four out of five had amplified a stretch of DNA that switches the androgen receptor on, sitting more than half a million letters away from the gene itself, where no ordinary test would look.

## Summary

Integrative deep whole-genome and whole-transcriptome analysis of 101 castration-resistant prostate cancer metastases, at 109-fold tumour and 38-fold normal coverage, identified structural variants altering critical regulators that exome approaches cannot detect. Amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor was present in 81% of patients and correlated with increased receptor expression. Tandem duplication hotspots also occurred near MYC, in long non-coding RNAs associated with post-translational MYC regulation. Classes of structural variation were linked to distinct DNA repair deficiencies: CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Cell
- Year: 2018
- DOI: 10.1016/j.cell.2018.06.039
- Authors: Quigley DA, Dang HX, Zhao SG, et al.
- Findings: An enhancer 624 kb upstream of AR amplified in 81% of 101 metastatic castration-resistant cancers, correlating with receptor expression.; Tandem duplication hotspots near MYC in long non-coding RNAs that regulate MYC after translation.; CDK12 mutation associated with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, BRCA2 inactivation with deletions.
- What it means: It shows that the commonest driver event in advanced prostate cancer is invisible to the panels used to test for it, and that the shape of the structural damage in a genome tells you which repair pathway failed, which is information a mutation list does not carry.
- Caveats: A hundred and one metastases from men with heavily treated disease, so it describes late disease rather than the whole spectrum.; Deep whole-genome sequencing of metastases is not available outside research.; Enhancer amplification is not reported by any clinical assay, so the finding cannot yet be acted on.

## Sources

- Quigley et al., Cell 2018: genomic hallmarks and structural variation in 101 metastatic castration-resistant prostate cancers (deep whole genomes): https://doi.org/10.1016/j.cell.2018.06.039
- PubMed: https://pubmed.ncbi.nlm.nih.gov/30033370/

## Connected records

- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [CDK12](https://onco.cc/targets/cdk12/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/)
- terms: [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Copy number alteration (CNA)](https://onco.cc/terms/copy-number-variation-term/), [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [Somatic mutations from exome and genome sequencing (WXS, WGS)](https://onco.cc/terms/somatic-mutations-wxs-wgs/)
- journals: [Cell](https://onco.cc/journals/cell/)
- biomarkers: [AR amplification (gene and upstream enhancer)](https://onco.cc/biomarkers/ar-amplification/)

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