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Two phase 2 trials, along with translational analysis of prospective cohorts and experimental analysis, indicate that immunosenescence as a mechanism of resistance to immunotherapy can be overcome with the senolytics dasatinib and quercetin in patients with head and neck squamous cell carcinoma.

Following androgen receptor pathway inhibition prostate cancers can differentiate towards the neuroendocrine lineage. Here, the authors identify epigenetic alterations regulated by ASCL1 and suggest targeting ASCL1 to reverse the neuroendocrine phenotype.

The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.

In a large multi-cancer cohort, a single liquid biopsy assay enables the detection of four epigenomic modifications, allowing the monitoring of expression of potential drug targets and resistance genes.

Sun Hur and colleagues examine the mechanism of Aire protein function underlying peripheral tissue antigen gene expression in thymic mTECs. They show that Aire condensates assemble on enhancers that are subject to intricate regulatory mechanisms, ensuring tight coordination of Aire CARD polymerization with genomic target recognition.

Here, the authors functionally characterize a complex genetic variant relevant in prostate cancer that regulates IRX4 expression through epigenetic activation. This work highlights the significance of non-single nucleotide polymorphism causal variants in explaining disease risk.

Epigenetic reprogramming of the androgen receptor (AR) has been identified as an important process driving prostate cancer (PCa) progression. Here, the authors analyze the role of AR chromatin binding heterogeneity in PCa clinical outcomes, metastasis and relapse.

Cistrome-wide association study (CWAS) is an approach for nominating variants that impact traits through effects on chromatin state. CWAS performed on 307 prostate cistromes identifies candidate loci for prostate cancer and androgen-related traits.

The authors reconstruct high fidelity networks of protein-protein interactions between promoters and enhancers in prostate cancer and demonstrate the potential of such an analytical framework to obtain actionable insights into the disease and potential therapeutic targets.

A machine-learning classifier predicts the origin of cancer of unknown primary based on electronic health records and next-generation sequencing data, showing that patients treated accordingly to model predictions had significantly better outcomes.

Ellis and colleagues show that combination of EZH2 inhibition and anti-PD-1 can increase antitumor immune responses in typically ‘immune cold’ prostate cancer, by increasing EZH2-regulated dsRNA–STING–ISG response signaling.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.

Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

HOXB13 suppresses a lipogenic transcriptional program in prostate cancer (PCa) through HDAC3 recruitment to enhancers. Loss of HOXB13 leads to lipid accumulation in PCa cells, promoting cell motility in vitro and xenograft tumor metastasis in vivo.

Analyses of epigenomic datasets spanning transitions from normal prostate epithelium to localized prostate cancer to metastases show that latent developmental programs are reactivated in metastatic disease and that prostate lineage-specific regulatory elements are strongly enriched for prostate cancer risk heritability.

Levi Garraway and colleagues report exome sequencing of 112 prostate adenocarcinomas and matched normal tissues. They identify novel recurrent mutations in several genes, including MED12, FOXA1 and SPOP. They find that tumors harboring SPOP mutations lack the TMPRSS2-ERG fusion or other ETS rearrangements, supporting the hypothesis that SPOP mutation is an early driver event in prostate tumorigenesis.

A cell-free DNA-methylation sequencing assay accurately identifies renal cell carcinoma using plasma and urine samples.

As the sample size in cancer genome studies increases, the list of genes identified as significantly mutated is likely to include more false positives; here, this problem is identified as stemming largely from mutation heterogeneity, and a new analytical methodology designed to overcome this problem is described.