Genomic hallmarks of localized, non-indolent prostate cancer

Abstract

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

“…This is significantly higher than in primary PCa, 6/498 patients (1.2%) ( Figure 1B and Table S3) (p<0.0001 Fisher exact test). Examination of data across additional primary and metastatic prostate cancer datasets revealed a similar difference in the frequency of biallelic CDK12 mutations between primary and metastatic cancer (Table S4) (Abida et al, 2017; Beltran et al, 2016; Fraser et al, 2017; Kumar et al, 2016). CRPC genomes are more highly mutated than those of localized tumors; however, the magnitude of the increased mutation rate is not sufficient to explain the increased frequency of biallelic loss of CDK12.…”

“…Comprehensive genomic analyses have substantially furthered our understanding of primary prostate cancer (PCa) and metastatic castration-resistant prostate cancer (mCRPC) (Barbieri et al, 2012; Beltran et al, 2016; Fraser et al, 2017; Grasso et al, 2012; Robinson et al, 2015; The Cancer Genome Atlas Research Network, 2015). These studies have discovered common genetic drivers of prostate cancer, such as fusions of ETS genes (Tomlins et al, 2005), amplification of AR , and loss of CDKN2A , PTEN , RB1 , SPOP , and TP53 (Robinson et al, 2015).…”

Treatment strategies for DNA repair-deficient prostate cancer

“…Notably, mutations in mismatch repair genes involved in fixing single-strand DNA breaks ( MSH2, MLH6 ) were very rare (<1%). A second study evaluating the genomic landscape of 477 localized intermediate-risk (Gleason 6–7) prostate cancers found that 47 patients (10%) harbored DNA repair mutations in homologous recombination genes: FANCA (n=9), ATM (n=8), RAD51 (n=7), CDK12 (n=6), and BRCA2 (n=5) [13]. Therefore, the prevalence of homologous recombination mutations in primary prostate cancer is likely between 8–10%.…”

The Heterogeneity of Prostate Cancer: A Practical Approach

“…A clear message as to the uniqueness of every patient's tumor from the major genetic characterization studies [32,33,34,37,38,39] raises the following questions: To what extent should we inform ourselves about the genetic alterations of every single tumor? Should we sequence every tumor's genome completely or retrieve information only about certain genes?…”