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

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

“…Approximately 30% of mCRPC patients with a homologous recombination deficiency signature lacked alterations in BRCA2 and other key homologous recombination genes. 32 Also, the neutrophil to lymphocyte ratio, a well-known prognostic factor in mCRPC was shown to be independently associated with worse outcomes after platinum therapy. 33 Our results should be viewed in the context of several limitations.…”

“…Homologous recombination deficiency signatures may also outperform BRCA2 as predictive biomarker, as BRCA1/2 may be silenced by methylation or posttranslational processes. Approximately 30% of mCRPC patients with a homologous recombination deficiency signature lacked alterations in BRCA2 and other key homologous recombination genes 32 . Also, the neutrophil to lymphocyte ratio, a well‐known prognostic factor in mCRPC was shown to be independently associated with worse outcomes after platinum therapy 33 …”

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer

“…We also tested this combination in the LNCaP/AR-Enh cell line, an isogenic derivative of parental LNCaP cells in which a second copy of the AR enhancer was introduced to the endogenous locus by genetic engineering 10 . AR enhancer duplication is an exceptionally pervasive somatic alteration in CRPC, found in up to 85% of cases 3,5 . We observed synergistic growth inhibition with furamidine and enzalutamide co-treatment in VCaP and 22Rv1 cells, which co-express AR and AR-Vs; notably, 22Rv1 cells are enzalutamide-resistant at baseline owing to high levels of AR-V7 21 .…”

“…Mechanisms leading to sustained AR signaling in CRPC include AR gene 2 and/or AR enhancer [3][4][5] amplification, activating point mutations in AR 6 , intra-tumoral steroid production, and synthesis of constitutively active truncated AR splice variants (AR-Vs) such as AR-V7 7 .…”

In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets

“…Mutational signatures based on the trinucleotide contexts of SNVs was performed, mainly using the MutationalPatterns package (1.10.0) 75 and as previously described. 67 The 96 Single…”