Temporal trends in medication and service use patterns for mental health issues among men with prostate cancer.

OBJECTIVE: Prostate cancer can significantly impact mental wellbeing, creating uncertainty and morbidity. This study described patterns of psychotropic medication and mental health service use, as a proxy measure for mental health problems, 5 years before and 5 years after prostate cancer diagnosis. METHODS: Population-based registry data were linked with Pharmaceutical Benefits Scheme and Medicare Benefits Schedule data for all prostate cancer patients diagnosed in South Australia between 2012 and 2020 (n = 13,693). We estimated the proportion and rates of psychotropic medication and mental health service use before and after diagnosis. Multivariable adjusted interrupted time series analyses (ITSA) were conducted to uncover temporal patterns. RESULTS: Fifteen percent of men commenced psychotropic medications and 6.4% sought out mental health services for the first time after diagnosis. Psychotropic medication use rose from 34.5% 5 years before to 40.3% 5 years after diagnosis, including an increase in use of antidepressants (from 20.7% to 26.0%) and anxiolytics (from 11.3% to 12.8%). Mental health service use increased from 10.2% to 12.1%, with the increase mostly being general practice mental health visits (from 7.8% to 10.6%). Multivariable ITSA indicated a significant rise in medication and service utilisation immediately before and in the first 2 years following prostate cancer diagnosis. CONCLUSION: There is a clear increase in psychotropic medication use and mental health service use around the time of prostate cancer diagnosis. Mental health outcomes of men with prostate cancer may be improved with early mental health screening, particularly during the diagnosis process, to enable early intervention.

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Impact of comorbidities on prostate cancer-specific mortality: A population-based cohort study.

AIM: To assess the impact of comorbidities on prostate cancer mortality. METHODS: We studied 15,695 South Australian men diagnosed with prostate cancer between 2003 and 2019 from state-wide administrative linked data sets. Comorbidity was measured 1-year before prostate cancer diagnosis using Rx-Risk, a medication-based comorbidity index. Flexible parametric competing risk regression was used to estimate the independent association between comorbidities and prostate cancer-specific mortality. Specific common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and pain) were also assessed to determine their association with mortality. All models were adjusted for sociodemographic variables, tumor characteristics, and treatment type. RESULTS: Prostate cancer-specific mortality was higher for patients with a Rx-Risk score ≥3 versus 0 (adjusted sub-hazard ratio (sHR) 1.34, 95% CI: 1.15-1.56). Lower comorbidity scores (Rx-Risk score 2 vs. 0 and Rx-Risk score 1 vs. 0) were not significantly associated with prostate cancer-specific mortality. Men who were using medications for cardiac disorders (sHR 1.31, 95% CI: 1.13-1.52), chronic airway disease (sHR 1.20, 95% CI: 1.01-1.44), depression and anxiety (sHR 1.17, 95% CI: 1.02-1.35), and thrombosis (sHR 1.21, 95% CI: 1.04-1.42) were at increased risk of dying from prostate cancer compared with men not on those medications. Use of medications for diabetes and chronic pain were not associated with prostate cancer-specific mortality. All Rx-Risk score categories and the specific comorbidities were also associated with increased risk of all-cause mortality. CONCLUSION: The findings showed that ≥3 comorbid conditions and specific comorbidities including cardiac disease, chronic airway disease, depression and anxiety, and thrombosis were associated with poor prostate cancer-specific survival. Appropriate management of these comorbidities may help to improve survival in prostate cancer patients.

Medication-based Comorbidity Measures and Prostate Cancer Treatment Selection.

INTRODUCTION: We aimed to assess the association between comorbidities and prostate cancer management. PATIENTS AND METHODS: We studied 12,603 South Australian men diagnosed with prostate cancer between 2003 and 2019. Comorbidity was measured one year prior to prostate cancer diagnosis using a medication-based comorbidity index (Rx-Risk). Binomial logistic regression analyses were used to assess the association between comorbidities and primary treatment selection (active surveillance, radical prostatectomy (RP), external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT), brachytherapy, ADT alone, and watchful waiting (WW)). Certain common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and chronic pain) were also assessed. All models were adjusted for sociodemographic and tumor characteristics. RESULTS: Likelihood of receiving RP was lower among men with Rx-Risk score ≥3 (odds ratio (OR) 0.62, 95%CI:0.56-0.69) and Rx-Risk 2 (OR 0.80, 95%CI:0.70-0.92) compared with no comorbidity (Rx-Risk ≤0). Men with high comorbidity (Rx-Risk ≥3) were more likely to have received ADT alone (OR 1.76, 95%CI:1.40-2.21), EBRT (OR 1.30, 95%CI:1.17-1.45) or WW (OR 1.49, 95%CI:1.19-1.88) compared with Rx-Risk ≤0. Pre-existing cardiac and respiratory disorders, thrombosis, diabetes, depression and anxiety, and chronic pain were associated with lower likelihood of selecting RP and higher likelihood of EBRT (except chronic airway disease) or WW (except diabetes and depression and anxiety). Cardiac disorders and thrombosis were associated with higher likelihood of selecting ADT alone. Furthermore, age had greater effect on treatment choice than the level of comorbidity. CONCLUSION: High comorbidity burden was associated with primary treatment choice, with significantly less RP and more EBRT, WW and ADT alone among men with higher levels of comorbidity. Each of the individual comorbid conditions also influenced treatment selection.

Acquired copy number variation in prostate tumours: a review of common somatic copy number alterations, how they are formed and their clinical utility.

Prostate cancer is one of the most commonly diagnosed cancers in men and unfortunately, disease will progress in up to a third of patients despite primary treatment. Currently, there is a significant lack of prognostic tests that accurately predict disease course; however, the acquisition of somatic chromosomal variation in the form of DNA copy number variants may help understand disease progression. Notably, studies have found that a higher burden of somatic copy number alterations (SCNA) correlates with more aggressive disease, recurrence after surgery and metastasis. Here we will review the literature surrounding SCNA formation, including the roles of key tumour suppressors and oncogenes (PTEN, BRCA2, NKX3.1, ERG and AR), and their potential to inform diagnostic and prognostic clinical testing to improve predictive value. Ultimately, SCNAs, or inherited germline alterations that predispose to SCNAs, could have significant clinical utility in diagnostic and prognostic tests, in addition to guiding therapeutic selection.

Utility of prescription-based comorbidity indices for predicting mortality among Australian men with prostate cancer.

BACKGROUND: Drug prescription registries has become an alternative data source to hospital admission databases for measuring comorbidities. However, the predictive validity of prescription-based comorbidity measures varies based on the population under investigation and outcome of interest. We aimed to determine which prescription-based index of comorbidity has most utility in Australian men with prostate cancer. METHODS: We studied 25,414 South Australian men diagnosed with prostate cancer between 2003 and 2019 from state-wide administrative linked datasets. The Rx-Risk index, Chronic Disease Score (CDS), Drug Comorbidity Index (DCI) and Pharmaceutical Prescribing Profile (P3) with one year lookback period from prostate cancer diagnosis were evaluated. The predictive ability of each index to determine all-cause deaths within two and five years of prostate cancer diagnosis was compared using the c-statistic from flexible parametric survival models, adjusting for age, socioeconomic status and year of prostate cancer diagnosis. RESULTS: The Rx-Risk index performed better in predicting two-year (c-statistic = 0.818) and five-year (c-statistic = 0.784) all-cause mortality than P3, CDS and DCI. Including comorbidity measures as continuous scores resulted in a better performance than including them as categories. Grouping scores into four categories (≤0, >0 - ≤1, >1 - ≤2, and >2) resulted in better performance and calibration than using fewer categories. CONCLUSION: Rx-Risk was validated in Australia and reflects Australian prescribing patterns. It showed better predictive performance for mortality in our study, with a modest improvement over P3, CDS and DCI. For research with prostate cancer populations, we recommend the use of drug-based comorbidity indices that have been validated in a similar population.

Risk of secondary malignancy following radiation therapy for prostate cancer.

We investigated whether prostate cancer patients treated with external beam radiation therapy (EBRT) have a higher cumulative incidence of secondary cancer compared with patients treated with radical prostatectomy (RP). We used state-wide linked data from South Australia to follow men with prostate cancer diagnosed from 2002 to 2019. The cumulative incidence of overall and site-specific secondary cancers between 5 and 15 years after treatment was estimated. Fine-Gray competing risk analyses were performed with additional sensitivity analyses to test different scenarios. A total of 7625 patients were included (54% underwent RP and 46% EBRT). Characteristics of the two groups differed significantly, with the EBRT group being older (71 vs. 64 years), having higher comorbidity burden and being more likely to die during follow-up than the RP group. Fifteen-year cumulative incidence for all secondary cancers was 27.4% and 22.3% in EBRT and RP groups, respectively. In the adjusted models, patients in the EBRT group had a significantly higher risk of genitourinary (adjusted subhazard ratio (aSHR), 2.29; 95%CI 1.16-4.51) and lung (aSHR, 1.93; 95%CI 1.05-3.56) cancers compared with patients in the RP group. However, there was no statistically significant difference between the two groups for risk of any secondary cancer, gastro-intestinal, skin or haematologic cancers. No statistically significant differences in overall risk of secondary cancer were observed in any of the sensitivity analyses and patterns for risk at specific cancer sites were relatively consistent across different age restriction and latency/time-lag scenarios. In conclusion, the increased risk of genitourinary and lung cancers among men undergoing EBRT may relate partly to treatment effects and partly to unmeasured residual confounding.

Predictive factors for treatment outcomes with intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema in clinical practice.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. METHODS: This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. RESULTS: There was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive "early functional response" (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an "early anatomical response", (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. CONCLUSIONS: The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. TRIAL REGISTRATION: The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 - 067).

Identification of a novel recurrent EEF2 gene amplification in familial prostate tumors.

Recurrent tumor copy number variations (CNVs) in prostate cancer (PrCa) have predominantly been discovered in sporadic tumor cohorts. Here, we examined familial prostate tumors for novel CNVs as prior studies suggest these harbor distinct CNVs. Array comparative genomic hybridization of 12 tumors from an Australian PrCa family, PcTas9, highlighted multiple recurrent CNVs, including amplification of EEF2 (19p13.3) in 100% of tumors. The EEF2 CNV was examined in a further 26 familial and seven sporadic tumors from the Australian cohort and in 494 tumors unselected for family history from The Cancer Genome Atlas (TCGA). EEF2 overexpression was observed in seven PcTas9 tumors, in addition to seven other predominantly familial tumors (ntotal  = 34%). EEF2 amplification was only observed in 1.4% of TCGA tumors, however 7.5% harbored an EEF2 deletion. Analysis of genes co-expressed with EEF2 revealed significant upregulation of two genes, ZNF74 and ADSL, and downregulation of PLSCR1 in both EEF2 amplified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 amplification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly amplified in familial tumors and deleted in unselected tumors. Our results provide further evidence that familial tumors harbor distinct CNVs, potentially due to an inherited predisposition, but also suggest that regardless of how EEF2 is dysregulated, a similar set of genes involved in key cancer pathways are impacted. Given the current lack of gene-based biomarkers and clinical targets in PrCa, further investigation of EEF2 is warranted.

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

The effect of insulin on response to intravitreal anti-VEGF injection in diabetic macular edema in type 2 diabetes mellitus.

OBJECTIVES: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. METHODS: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. RESULTS: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05). CONCLUSION: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.

Urban-rural prostate cancer disparities in a regional state of Australia.

Men living in regional and remote areas experience disparities in prostate cancer (PrCa) diagnosis, clinical characteristics and treatment modalities. We sought to determine whether such disparities exist in PrCa patients from Tasmania; a regional state of Australia with the second-highest rate of diagnosis and where over a third of residents live in outer regional and remote areas. Our study included clinicopathological data from 1526 patients enrolled in the Prostate Cancer Outcomes Registry-Tasmania. Regression analyses were undertaken to determine whether demographic, clinical and treatment variables differed between inner regional and outer regional/remote patients. Men from outer regional/remote areas were significantly more likely to reside in lower socio-economic areas, be diagnosed at a later age and with more clinically aggressive features. However, in contrast to previous studies, there were no overall differences in diagnostic or treatment method, although men from outer regional/remote areas took longer to commence active treatment and travelled further to do so. This study is the first to investigate PrCa disparities in a wholly regional Australian state and highlights the need to develop systematic interventions at the patient and healthcare level to improve outcomes in outer regional and remote populations in Australia and across the globe.

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition.

There is strong interest in the characterisation of gene fusions and their use to enhance clinical practices in prostate cancer (PrCa). Significantly, ~50% of prostate tumours harbour a gene fusion. Inherited factors are thought to predispose to these events but, to date, only one study has investigated gene fusions in a familial context. Here, we examined the prevalence and diversity of gene fusions in 14 tumours from a single large PrCa family, PcTas9, using the TruSight® RNA Fusion Panel and Sanger sequencing validation. These fusions were then explored in The Cancer Genome Atlas (TCGA) PrCa data set (n = 494). Overall, 64.3% of PcTas9 tumours harboured a gene fusion, including known erythroblast transformation-specific (ETS) fusions involving ERG and ETV1, and two novel gene fusions, C19orf48:ETV4 and RYBP:FOXP1. Although 3' ETS genes were overexpressed in PcTas9 and TCGA tumour samples, 3' fusion of FOXP1 did not appear to alter its expression. In addition, PcTas9 fusion carriers were more likely to have lower-grade disease than noncarriers (p = 0.02). Likewise, TCGA tumours with high-grade disease were less likely to harbour fusions (p = 0.03). Our study further implicates an inherited predisposition to PrCa gene fusion events, which are associated with less aggressive tumours. This knowledge could lead to clinical strategies to predict men at risk for fusion-positive PrCa and, thus, identify patients who are more or less at risk of aggressive disease and/or responsive to particular therapies.

Evaluation of Hypofractionated Radiation Therapy Use and Patient-Reported Outcomes in Men With Nonmetastatic Prostate Cancer in Australia and New Zealand.

Importance: Randomized clinical trials in prostate cancer have reported noninferior outcomes for hypofractionated radiation therapy (HRT) compared with conventional RT (CRT); however, uptake of HRT across jurisdictions is variable. Objective: To evaluate the use of HRT vs CRT in men with nonmetastatic prostate cancer and compare patient-reported outcomes (PROs) at a population level. Design, Setting, and Participants: Registry-based cohort study from the Australian and New Zealand Prostate Cancer Outcomes Registry (PCOR-ANZ). Participants were men with nonmetastatic prostate cancer treated with primary RT (excluding brachytherapy) from January 2016 to December 2019. Data were analyzed in March 2021. Exposures: HRT defined as 2.5 to 3.3 Gy and CRT defined as 1.7 to 2.3 Gy per fraction. Main Outcomes and Measures: Temporal trends and institutional, clinicopathological, and sociodemographic factors associated with use of HRT were analyzed. PROs were assessed 12 months following RT using the Expanded Prostate Cancer Index Composite (EPIC)-26 Short Form questionnaire. Differences in PROs were analyzed by adjusting for age and National Comprehensive Cancer Network risk category. Results: Of 8305 men identified as receiving primary RT, 6368 met the inclusion criteria for CRT (n = 4482) and HRT (n = 1886). The median age was 73.1 years (IQR, 68.2-77.3 years), 2.6% (168) had low risk, 45.7% (2911) had intermediate risk, 44.5% (2836) had high-/very high-risk, and 7.1% (453) had regional nodal disease. Use of HRT increased from 2.1% (9 of 435) in the first half of 2016 to 52.7% (539 of 1023) in the second half of 2019, with lower uptake in the high-/very high-risk (1.9% [4 of 215] to 42.4% [181 of 427]) compared with the intermediate-risk group (2.2% [4 of 185] to 67.6% [325 of 481]) (odds ratio, 0.26; 95% CI, 0.15-0.45). Substantial variability in the use of HRT for intermediate-risk disease remained at the institutional level (median 53.3%; range, 0%-100%) and clinician level (median 57.9%; range, 0%-100%) in the last 2 years of the study period. There were no clinically significant differences across EPIC-26 urinary and bowel functional domains or bother scores. Conclusions and Relevance: In this cohort study, use of HRT for prostate cancer increased substantially from 2016. This population-level data demonstrated clinically equivalent PROs and supports the continued implementation of HRT into routine practice. The wide variation in practice observed at the jurisdictional, institutional, and clinician level provides stakeholders with information that may be useful in targeting implementation strategies and benchmarking services.

Comparing vision and macular thickness in neovascular age-related macular degeneration, diabetic macular oedema and retinal vein occlusion patients treated with intravitreal antivascular endothelial growth factor injections in clinical practice.

OBJECTIVE: To compare the visual outcomes of intravitreal antivascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in a real-world setting. METHODS AND ANALYSIS: Retrospective analysis of data from the Tasmanian Ophthalmic Biobank database. The median change in best-corrected visual acuity (BCVA) between baseline and 12 months post initiating intravitreal anti-VEGF treatment were compared between the three diseases. Final BCVA, central macular thickness (CMT), cumulative number of injections and overall predictors of change in BCVA and CMT were also determined. RESULTS: At 12 months, change in BCVA was significantly different between nAMD, DMO and RVO cohorts (p=0.032), with lower median change for DMO (2 letters, range -5 to 20) than for RVO (11 letters, range -20 to 35). Likewise, CMT change was significantly different between the three cohorts (p=0.022), with a smaller reduction in CMT in DMO (-54 µm, range -482 to 50) than RVO patients (-137 µm, range -478 to 43; p=0.033). Total number of injections received (p=0.028) and final BCVA score (p=0.024) were also significantly different between the groups. Baseline BCVA was a negative predictor (p=0.042) and baseline CMT a positive predictor (p<0.001) of outcome. After adjusting for baseline BCVA and CMT, diagnosis of nAMD or RVO was a predictor of visual improvement compared with the DMO. CONCLUSIONS: At the end of 12 months, nAMD and RVO cohorts had the greatest improvement in BCVA, however the final BCVA for DMO was significantly better than for nAMD.

A rare variant in EZH2 is associated with prostate cancer risk.

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10-5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.