Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

A novel interaction between RNA m6A methyltransferase METTL3 and RREB1.

Regulation of gene expression is achieved through the modulation of regulatory inputs both pre- and post-transcriptionally. Methyltransferase-like 3 (METTL3) is a key player in pre-mRNA processing, actively catalyzing N6-methyladenosine (m6A). Among the most enriched mRNA targets of METTL3 is the Ras Responsive Element Binding Protein 1 (RREB1), a transcription factor which functions to govern cell fate, proliferation and DNA repair. Here, we show a novel interaction between METTL3 and RREB1. Further examination of this interaction indicates that METTL3's N-terminus is the primary interacting domain. Our findings uncover a novel interacting partner of METTL3, providing further insights into METTL3's regulatory network.

Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas.

TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.

The psychosocial burdens of living with diabetes.

AIM: To better understand the prevalence of self-reported psychosocial burdens and the unmet needs identified by people with diabetes in relation to routine diabetes visits. METHODS: An English language, online survey was distributed via social media, key stakeholder networks, charity and advocacy groups to adults with type 1 diabetes or type 2 diabetes. Survey items were designed by members of the FDA RESCUE Collaborative Community Governing Committee prior to pilot testing with potential participants. Descriptive statistical analyses were conducted, as well as thematic analyses on free-text responses using NVivo v14. RESULTS: Four hundred and seventy-eight participants completed the survey: 373 (78%) had type 1 diabetes, 346 (73%) identified as a woman and 433 (91%) were white. Most participants had experienced self-reported (rather than diagnosed) anxiety and depression (n = 323 and n = 313, respectively), as well as fear of low blood sugars (n = 294), low mood (n = 290) and diabetes-related distress (n = 257). Sixty-eight percent reported that diabetes had negatively affected self-esteem, 62% reported the feelings of loneliness, but 93% reported that friends/family/work colleagues were supportive when needed. Two hundred and seventy-two percent (57%) reported that their diabetes team had never raised the topic of mental health. The overwhelming majority stated that the best thing their diabetes team could do to help was to simply ask about mental well-being, listen with empathy and without judgement, and practice skills to understand psychosocial issues in diabetes. CONCLUSION: Integrating psychosocial discussions and support within routine healthcare visits is crucial to improve outcomes for people with diabetes. Such a biopsychosocial model of healthcare has long been advocated by regulatory bodies.

Quality of life outcomes for patients with metastatic castration-resistant prostate cancer and pretreatment prognostic score.

BACKGROUND: A prognostic risk score (Halabi score) in metastatic castration-resistant prostate cancer (mCRPC) accurately predicts overall survival, but its association with quality of life (QOL) has not been defined. We hypothesize that a higher pretreatment Halabi score is associated with worse QOL outcomes over time in mCRPC patients. METHODS: Patient-level data from the docetaxel plus prednisone control arm of Mainsail, a Phase 3 clinical trial in mCRPC were accessed via ProjectDataSphere. Pretreatment Halabi score included disease-related factors: metastatic site, opioid use, Eastern Cooperative Oncology Group performance status (ECOG-PS), alkaline phosphatase, albumin, hemoglobin, lactic acid dehydrogenase, and PSA, with higher score indicating worse survival. Three QOL scales were created: Functional Assessment of Cancer Therapy-Prostate (FACT-P, higher score = better QOL), Brief Pain Inventory-Short Form Severity score (BPI-SFSS, higher score = higher pain severity), and BPI-SF Interference score (BPI-SFIS, higher score = greater pain interference). Mixed linear model was used to estimate the associations between Halabi score and QOL scores assessed at different time points (baseline, 2 months, and 6 months). RESULTS: This analysis included 412 mCRPC patients (median age = 68 years, 82% white, 5% Black, median log PSA = 4.4 ng/mL). After multivariable adjustment, Halabi score was significantly associated with QOL scores at all time points. At 6 months, multivariable adjusted FACT-P decreased by 10.0 points (worsening), BPI-SFSS increased by 0.8 points (worsening), and BPI-SFIS increased by 0.9 points (worsening) for each unit increase in Halabi risk score. In multivariable analysis of individual components, ECOG-PS, site of metastasis, and opioid use were significantly associated with worse QOL scores at baseline. CONCLUSIONS: Chemotherapy-naïve mCRPC patients with poorer Halabi prognostic risk scores have poorer QOL and greater pain intensity and interference at baseline and during follow-up.

Clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with abiraterone with or without ongoing androgen deprivation therapy: A retrospective case-control study.

INTRODUCTION: Abiraterone and concurrent androgen deprivation therapy (ADT) are used in the treatment of patients with metastatic castration-resistant prostate cancer. Recently, it has been suggested that the use of abiraterone alone (without ADT) may have comparable efficacy to abiraterone with ongoing ADT. Here, we sought to assess the impact of ADT cessation in patients beginning abiraterone for castration-resistant prostate cancer. METHODS: We identified 39 patients at our institution who received abiraterone alone (with discontinuation of ADT) between 2011 and 2022. We then procured a comparable group of 39 patients (matched by age, Gleason score, and prostate-specific antigen [PSA] level) who received abiraterone with ongoing ADT during the same period. We assessed and compared clinical outcomes in the two groups (abiraterone-alone vs. abiraterone-ADT) with respect to PSA response rates, PSA progression-free survival, and overall survival. Results were adjusted using Cox proportional-hazards multivariable models. RESULTS: The median PSA before treatment initiation was 12.7 (range: 0.2-199) ng/mL in the abiraterone-alone group and 15.5 (range: 0.6-212) ng/mL in the abiraterone-ADT group. Use of abiraterone alone adequately suppressed testosterone levels in 35/37 (94.6%) patients. Patients receiving abiraterone alone had a median PSA reduction of 80.2% versus 79.5% in patients receiving abiraterone plus ADT. The median PSA progression-free survival in patients receiving abiraterone alone was 27.4 versus 25.8 months in patients receiving abiraterone plus ADT (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.65-1.71; p = 0.82). In addition, abiraterone alone was associated with an overall survival of 3.6 versus 3.1 years in patients receiving abiraterone plus ADT (HR 0.90; 95% CI 0.50-1.62; p = 0.72). There were no differences in PFS or OS between groups after performing Cox multivariable regression analyses. CONCLUSION: Use of abiraterone alone was associated with comparable clinical outcomes to patients who received abiraterone together with ADT. Further prospective studies are warranted to evaluate the impact of abiraterone alone on treatment outcomes and cost savings.

Comprehensive genomic profiling of penile squamous cell carcinoma and the impact of human papillomavirus status on immune-checkpoint inhibitor-related biomarkers.

BACKGROUND: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune-checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection. METHODS: Evaluation was done retrospectively of the landscape of somatic alterations and ICI-related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV-dependent oncogenesis. The pSCC tumors were analyzed by using next-generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD-L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)-high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole-exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (q value < .05). RESULTS: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD-L1+, 10.7% had high TMB, and 1.1% had mismatch repair-deficient (dMMR)/MSI-high status. Twenty-nine patients had their HPV status made available by WES (HPV16/18+, n = 13; HPV16/18-, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18+ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18- tumors. TMB-high was exclusively found in the HPV16/18+ group (30.8%). The two groups had comparable PD-L1 and dMMR/MSI-H status. CONCLUSIONS: In a large and comprehensive NGS-based evaluation of somatic alterations in pSCC, HPV16/18+ versus HPV16/18- pSCCs were molecularly distinct tumors. Our finding that TMB-high is exclusive to HPV16/18+ tumors requires confirmation in larger data sets. PLAIN LANGUAGE SUMMARY: Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune-checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined. Using next-generation sequencing, we explored the genetic landscape and ICI-related biomarkers of pSCC and HPV-driven oncogenic molecular signatures. Our results indicate that HPV-positive and HPV-negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV-positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI-based therapies. Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI-based clinical trials.

H2A monoubiquitination: insights from human genetics and animal models.

Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.