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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.
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.
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.
Shares CDK12, Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares AR amplification (gene and upstream enhancer), Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC), Androgen receptor.
Shares Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), Androgen receptor, RNA sequencing & expression profiling.
Shares Copy number alteration (CNA), Chromosomal instability & aneuploidy, Androgen receptor signalling, Androgen receptor.
Shares Copy number alteration (CNA), Chromosomal instability & aneuploidy, Androgen receptor signalling, Androgen receptor.
Shares AR amplification (gene and upstream enhancer), Gene amplification and copy-number change, Androgen receptor signalling, Castration-resistant prostate cancer (CRPC).
Shares Copy number alteration (CNA), Chromosomal instability & aneuploidy, Castration-resistant prostate cancer (CRPC), Androgen receptor.