Defining a "Good Death": Exploring Veterinarians' Perceptions of Companion Animal Euthanasia.

This study was designed to determine how veterinarians define a good euthanasia experience. This information is used to generate a working definition of companion animal euthanasia that aligns with animal welfare standards and pet owners' expectations. An electronic survey distributed via veterinary-related social media (Facebook, Instagram) and listservs were completed by 249 veterinarians who perform feline and/or canine euthanasia. Our results suggest that very few veterinarians feel their veterinary school training adequately prepared them for euthanasia. When veterinarians were asked to rank a list of physiologic conditions and anatomical traits in order of euthanasia-related concerns, respiratory distress was ranked the highest, while the most concerning physical changes were reported to be indications or impressions of seizures or pain. The most commonly reported euthanasia injection technique performed by participants was intravenous administration of pentobarbital sodium (97%), and most veterinarians preferred having owners present (57%) or having no preference (38%) during euthanasia. Results suggest that veterinarians want a pain-free, anxiety-free experience for the patient, appreciate the use of sedatives before euthanasia, and feel that when available and appropriate, home euthanasia offers several benefits. This understanding of the numerous aspects involved in a good euthanasia experience can help inform the creation of an updated definition of companion animal euthanasia that strives to prioritize the welfare of the patient as well as the needs and expectations of the pet owner.

Clinician interest in clinical decision support for PSA-based prostate cancer screening.

OBJECTIVE: To evaluate the interest of primary care clinicians in utilizing CDS for PSA screening. Evidence suggests that electronic clinical decision support (CDS) may decrease low-value prostate-specific antigen (PSA) testing. However, physician attitudes towards CDS for PSA screening are largely unknown. METHODS: A survey was sent to 201 primary care clinicians, including both physicians and Advanced Practice Providers (APP), within a large academic health system. Eligible clinicians cared for male patients aged 40 to 80 years and ordered ≥5 PSA tests in the past year. Respondents were stratified into 3 groups, appropriate screeners, low-value screeners, or rare-screeners, based on responses to survey questions assessing PSA screening practices. The degree of interest in electronic CDS was determined via a composite Likert score comprising relevant survey items. RESULTS: Survey response rate was 29% (59/201) consisting of 85% MD/DO and 15% APP respondents. All clinicians surveyed were interested in CDS (P < 0.001) without significant difference between screener groups. Clinicians agreed most uniformly that CDS be evidence-based. Clinicians disagreed on whether CDS would decrease professional discretion over patient decisions. CONCLUSIONS: Primary care clinicians are interested in CDS for PSA screening regardless of their current screening practices. Prioritizing CDS features that clinicians value, such as ensuring CDS recommendations are evidence-based, may increase the likelihood of successful implementation, whereas perceived threat to autonomy may be a hinderance to utilization.

Initial outcomes and insights from a novel high-risk prostate cancer screening clinic.

INTRODUCTION: Guidelines for germline testing in patients with prostate cancer (PCa) are identifying family members who require additional surveillance given pathogenic variants (PVs) that confer increased PCa risk. We established an interdisciplinary clinic for cancer surveillance in high-risk individuals aimed to implement screening recommendations. This study aimed to characterize the clinical features of this cohort. PATIENTS AND METHODS: The Prostate Cancer Risk Clinic (PCRC) was established for unaffected individuals with germline PVs or a strong PCa family history. PCa screening, urine labs, and questionnaires were included in the visit. Individuals with BRCA1/2 PVs underwent clinical breast exam as well. Data from the initial visit were abstracted from the medical record and questionnaires for analysis. RESULTS: Thirty-five individuals with increased PCa risk were followed by the PCRC with a median age of 47 years of age. Twenty individuals (57%) had a family history of PCa, and 34 (97%) had a germline PV associated with an increased risk for developing PCa. Four individuals underwent biopsy due to care in the PCRC, with one PCa identified in an individual with TP53 PV. Median patient response scores indicated mild symptoms of an enlarged prostate (AUASS), normal erectile function (SHIM), and relatively low anxiety about developing PCa (MAX-PC). However, there were notable "outlier" scores on each questionnaire. CONCLUSIONS: Individuals with prostates and BRCA1/2 PVs, among other germline PVs, can benefit from a comprehensive interdisciplinary approach to high-risk management. PCa was identified in an individual with a non-BRCA PV, emphasizing the importance and need for high-risk screening guidelines across all genes with increased risk for PCa. "Outlier" patient response scores demonstrate that some participants experienced worse symptoms or anxiety than was indicated by median scores alone.

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry.

BACKGROUND: Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. METHODS: Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤ 0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1184) from the UK Biobank (UKB). RESULTS: Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), pexact = 7.01E-06, FDR-adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact = 5.51E-06, FDR-adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact = 0.19. However, IGF1R R511Q was not found in cases or controls. CONCLUSIONS: This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Reliability of Ancestry-specific Prostate Cancer Genetic Risk Score in Four Racial and Ethnic Populations.

Background: Reliability of prostate cancer (PCa) genetic risk score (GRS), that is, the concordance between its estimated risk and observed risk, is required for genetic testing at the individual level. Reliability data are lacking for non-European racial/ethnic populations, which hinders its clinical use and exacerbates racial disparity. Objective: To calibrate PCa ancestry-specific GRS in four racial/ethnic populations. Design setting and participants: PCa ancestry-specific GRSs, calculated from published risk-associated single-nucleotide polymorphisms in corresponding racial/ethnic populations, were evaluated in men who participated in 23andMe, Inc. genetic testing and consented for research, including 888 086 of European (EUR), 81 109 of Hispanic (HIS), 30 472 of African (AFR), and 13 985 of East Asian (EAS) ancestry, as classified by 23andMe's ancestry composition algorithm. Outcome measurements and statistical analysis: The concordance between the observed and estimated PCa risks at ten ancestry-specific GRS deciles was measured primarily by using the calibration slope (ß), where 1 represents a perfect calibration. Platt scaling was used to correct the systematic bias of GRS. Results and limitations: A linear trend of an increased observed PCa prevalence in men with higher ancestry-specific GRS deciles was found in each racial population (all p -trend < 0.001). A calibration analysis revealed a systematic bias of GRS; ß was considerably lower than 1 (0.73, 0.64, 0.66, and 0.75 in EUR, HIS, AFR, and EAS ancestries, respectively). This bias was reduced after the Platt scaling correction: ß for scaled GRS in the testing dataset (40% of individuals) approximated 1 for all groups (0.95, 1.05, 1.02, and 1.01 in EUR, HIS, AFR, and EAS populations, respectively). The generalizability of the Platt correction needs to be validated in independent cohorts. Conclusions: A systematic bias of ancestry-specific GRS in the direction of an overestimated risk for men in the highest decile was found in EUR and non-EUR populations. GRS is well calibrated after correction and is appropriate for genetic testing at the individual level for personalized PCa screening. Patient summary: A corrected genetic risk score is more reliable (supported by the observed prostate cancer [PCa] risk) and appropriate for genetic testing for personalized PCa screening.

Germline Variants in DNA Damage Repair Genes and HOXB13 Among Black Patients With Early-Onset Prostate Cancer.

PURPOSE: Genetic studies of prostate cancer susceptibility have predominantly focused on non-Hispanic White men, despite the observation that Black men are more likely to develop prostate cancer and die from the disease. Therefore, we sought to identify genetic variants in Black patients diagnosed with early-onset prostate cancer. METHODS: Whole-exome sequencing of germline DNA from a population-based cohort of Black men diagnosed with prostate cancer at age 62 years or younger was performed. Analysis was focused on a panel of DNA damage repair (DDR) genes and HOXB13. All discovered variants were ranked according to their pathogenic potential based upon REVEL score, evidence from existing literature, and prevalence in the cohort. Logistic regression was used to investigate associations between mutation status and relevant clinical characteristics. RESULTS: Among 743 Black prostate cancer patients, we identified 26 unique pathogenic (P) or likely pathogenic (LP) variants in 14 genes (including HOXB13, BRCA1/2, BRIP1, ATM, CHEK2, and PALB2) among 30 men, or approximately 4.0% of the patient population. We also identified 33 unique variants of unknown significance in 16 genes among 39 men. Because of the rarity of these variants in the population, most associations between clinical characteristics did not achieve statistical significance. However, our results suggest that carriers for P or LP (P/LP) variants were more likely to have a first-degree relative diagnosed with DDR gene-associated cancer, have a higher prostate-specific antigen at time of diagnosis, and be diagnosed with metastatic disease. CONCLUSION: Variants in DDR genes and HOXB13 may be important cancer risk factors for Black men diagnosed with early-onset prostate cancer, and are more frequently observed in men with a family history of cancer.

KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.

BACKGROUND: Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations. METHODS: Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using a logistic regression model adjusting for genetic background (top ten principal components). RESULTS: In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression. CONCLUSIONS: Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.

Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis. METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models. RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers. CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients.

BACKGROUND: Recently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men. METHODS: We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital. RESULTS: Seven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case-case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00-28.52, P = 0.03). CONCLUSIONS: While this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population.

The use of intrarenal injection of sodium pentobarbital for euthanasia in cats.

OBJECTIVE: To determine whether intrarenal injection of sodium pentobarbital is a viable method for euthanasia in anesthetized client-owned cats and assess potential factors associated with time to cardiopulmonary arrest (TCPA) for such treated cats. ANIMALS: 131 client-owned cats. PROCEDURES: In this retrospective study, client-owned cats presented for euthanasia between March 1, 2009, and January 15, 2010, were evaluated by veterinarians to determine suitability of intrarenal injection versus other methods of euthanasia. Cats included were anesthetized and then received 6 mL of sodium pentobarbital (390 mg/mL) by intrarenal injection. Results for TCPA were compared for cats grouped on the basis of variables of interest. RESULTS: 131 cats were included, of which 74 (79%) had a TCPA < 1 minute and 28 (21%) had a TCPA between 1.5 and 8 minutes after intrarenal injection. Most (124/131 [95%]) cats had no observable reaction to the intrarenal injection other than cardiopulmonary arrest. Median TCPA was longer for cats without (1 min; 25/131 [19%]) versus with (0 min; 106/131 [81%]) palpable kidney swelling upon injection. CLINICAL RELEVANCE: The effects of intrarenal injection of sodium pentobarbital in cats of the present study were similar to those typically observed with IV administration of euthanasia solution. When this intrarenal injection method is used, cardiopulmonary arrest with few agonal reactions can be expected to occur quickly in most patients. The intrarenal injection method is suited for euthanasia of anesthetized cats with easily located kidneys when IV access may be difficult.

Prostate Cancer Predisposition.

The identification and characterization of alterations in prostate cancer (PCa)-predisposing genes can help to inform screening strategies in undiagnosed men and treatment options in men in both the clinically localized and in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PCa, the current role of genetics and PCa risk assessment, and how genetic risk factors affect aggressiveness and lethality of PCa.

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

BACKGROUND: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. METHODS: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction. RESULTS: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). CONCLUSION: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.

Pet Owners' Expectations for Pet End-of-Life Support and After-Death Body Care: Exploration and Practical Applications.

Pet owners caring for a pet during the end of its life are faced with aftercare choices and decisions. This study, through the use of an online anonymous survey, explored the perceptions and expectations of United States (US) pet owners regarding end-of-life issues, with a focus on after-death body care. Participants living in the US who were the current owners of at least one cat or dog, had a regular veterinarian, and had made end-of-life decisions for at least one pet were recruited for the study. Survey respondents included 2043 dog and/or cat owners (41.4% male, 57.9% female) of which 68% had made cremation decisions and 32% had made burial decisions for at least one pet in the past. The majority of these owners indicated they preferred to work with a specific crematory (43%) or cemetery (70%) and over 95% of these owners reported feeling it important to work with their preferred after-death body care service. In terms of guidance, most owners indicated they rely on their veterinary team to help them with end-of-life decisions and orchestrating arrangements on their behalf with tertiary pet aftercare services/companies. Participants indicated being more likely to use veterinary staff for pet death and dying as well as after-death body care and memorialization than any other source. When asked about these after-death body care conversations, 73% indicated they need 20 minutes or less. Participants expressed significant concern over several aspects of after-death body care (e.g., body mislabeling, type of container used for short term and long-term storage). Results of this study create the foundation for practical, ethical after-death body care recommendations to help guide veterinary teams acting on their clients' behalf.

Performance of Three Inherited Risk Measures for Predicting Prostate Cancer Incidence and Mortality: A Population-based Prospective Analysis.

BACKGROUND: Single nucleotide polymorphism-based genetic risk score (GRS) has been developed and validated for prostate cancer (PCa) risk assessment. As GRS is population standardized, its value can be interpreted as a relative risk to the general population. OBJECTIVE: To compare the performance of GRS with two guideline-recommended inherited risk measures, family history (FH) and rare pathogenic mutations (RPMs), for predicting PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort was derived from the UK Biobank where 208 685 PCa diagnosis-free participants at recruitment were followed via the UK cancer and death registries. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rate ratios (RRs) of PCa incidence and mortality for FH (positive vs negative), RPMs (carriers vs noncarriers), and GRS (top vs bottom quartile) were measured. RESULTS AND LIMITATIONS: After a median follow-up of 9.67 yr, 6890 incident PCa cases (419 died of PCa) were identified. Each of the three measures was significantly associated with PCa incidence in univariate analyses; RR (95 % confidence interval [CI]) values were 1.88 (1.75-2.01) for FH, 2.89 (1.89-4.25) for RPMs, and 1.97(1.87-2.07) for GRS (all p < 0.001). The associations were independent in multivariable analyses. While FH and RPMs identified 11 % of men at higher PCa risk, addition of GRS identified an additional 22 % of men at higher PCa risk, and increases in C-statistic from 0.58 to 0.67 for differentiating incidence (p < 0.001) and from 0.65 to 0.71 for differentiating mortality (p = 0.002). Limitations were a small number of minority patients and short mortality follow-up. CONCLUSIONS: This population-based prospective study suggests that GRS complements two guideline-recommended inherited risk measures (FH and RPMs) for stratifying the risk of PCa incidence and mortality. PATIENT SUMMARY: In a large population-based prostate cancer (PCa) prospective study derived from UK Biobank, genetic risk score (GRS) complements two guideline-recommended inherited risk measures (family history and rare pathogenic mutations) in predicting PCa incidence and mortality. These results provide critical data for including GRS in PCa risk assessment.

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer.

PURPOSE: Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. PATIENTS AND METHODS: To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. RESULTS: All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations. CONCLUSION: These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.

Germline HOXB13 G84E mutation carriers and risk to twenty common types of cancer: results from the UK Biobank.

Germline HOXB13 G84E mutation has been consistently associated with prostate cancer (PCa) risk, but its association with other cancers is controversial. We systematically tested its association with the 20 most common cancer types in subjects from the UK Biobank. The G84E mutation was found in 1,545 (0.34%) of 460,224 participants of European ancestry. While mutation status did not associate with cancer risk in females, it was significantly associated with increased risk in males; odds ratio (OR) (95% confidence interval) for overall cancer diagnosis was 2.19 (1.89-2.52), P = 2.5E-19. The association remained after excluding PCa; OR = 1.4 (1.16-1.68), P = 0.003, suggesting association with other cancers. Indeed, suggestive novel associations were found for two other cancer types; rectosigmoid cancer, OR = 2.25 (1.05-4.15), P = 0.05 and non-melanoma skin cancer (NMSC), OR = 1.40 (1.12-1.74), P = 0.01. For NMSC, the association was found only in basal cell carcinoma, OR = 1.37 (1.07-1.74), P = 0.03. These findings have potential clinical utility for genetic counselling regarding HOXB13.

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.