Functional characterization of 5p15.33 risk locus in uveal melanoma reveals rs452384 as a functional variant and NKX2.4 as an allele-specific interactor.

The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide association study in uveal melanoma (UM), which uncovered a role for the TERT/CLPTM1L risk locus in this intraocular tumor and identified multiple highly correlated risk alleles. Aiming to unravel the biological mechanisms in UM of this locus, which contains a domain enriched in active chromatin marks and enhancer elements, we demonstrated the allele-specific enhancer activity of this risk region using reporter assays. In UM, we identified the functional variant rs452384, of which the C risk allele is associated with higher gene expression, increased CLPTM1L expression in UM tumors, and a longer telomere length in peripheral blood mononuclear cells. Electrophoretic mobility shift assays and quantitative mass spectrometry identified NKX2.4 as an rs452384-T-specific binding protein, whereas GATA4 preferentially interacted with rs452384-C. Knockdown of NKX2.4 but not GATA4 resulted in increased TERT and CLPTM1L expression. In summary, the UM risk conferred by the 5p locus is at least partly due to rs452384, for which NKX2.4 presents strong differential binding activity and regulates CLPTM1L and TERT expression. Altogether, our work unraveled some of the complex regulatory mechanisms at the 5p15.33 susceptibility region in UM, and this might also shed light on shared mechanisms with other tumor types affected by this susceptibility region.

Virtual Injection Software Reduces Radiation Exposure and Procedural Time of Prostatic Artery Embolization Performed with Cone-Beam CT.

PURPOSE: To evaluate the impact of virtual injection software (VIS) use during cone-beam computed tomography (CT)-guided prostatic artery embolization (PAE) on both patient radiation exposure and procedural time. MATERIALS AND METHODS: This institutional review board (IRB)-approved comparative retrospective study analyzed the treatment at a single institution of 131 consecutive patients from January 2020 to May 2022. Cone-beam CT was used with (Group 1, 77/131; 58.8%) or without VIS (Group 2, 54/131, 41.2%). Radiation exposure (number of digital subtraction angiography [DSA] procedures), dose area product (DAP), total air kerma (AK), peak skin dose (PSD), fluoroscopy time (FT), and procedure time (PT) were recorded. The influences of age, body mass index, radial access, and use of VIS were assessed. RESULTS: In bivariate analysis, VIS use (Group 1) showed reduction in the number of DSA procedures (8.6 ± 3.7 vs 16.8 ± 4.3; P < .001), DAP (110.4 Gy·cm2 ± 46.8 vs 140.5 Gy·cm2 ± 61; P < .01), AK (642 mGy ± 451 vs 1,150 mGy ± 637; P = .01), PSD (358 mGy ± 251 vs 860 mGy ± 510; P = .001), FT (35.6 minutes ± 15.4 vs 46.6 minutes ± 20; P = .001), and PT (94.6 minutes ± 41.3 vs 115.2 minutes ± 39.6, P = .005) compared to those in Group 2. In multivariate analysis, AK, PSD, FT, and PT reductions were associated with VIS use (P < .001, P < .001, P = .001, and P = .006, respectively). CONCLUSIONS: The use of VIS during PAE performed under cone-beam CT guidance led to significant reduction in patient radiation exposure and procedural time.

Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.

Clinical performance of magnetic resonance imaging and biomarkers for prostate cancer diagnosis in men at high genetic risk.

OBJECTIVES: To evaluate different scenarios for the management of early diagnosis of cancer (PCa) in men at high genetic risk, using recently developed blood and urinary molecular biomarkers in combination with clinical information alongside multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: A total of 322 patients with a high genetic risk (familial or personal history of cancers or a predisposing germline variant) were included in this study. The primary outcome was the detection rates of PCa (positive biopsy) or clinically significant PCa (biopsy with International Society of Urological Pathology [ISUP] grade >1). Clinical parameters included age, body mass index, ancestry, and germline mutational status, mpMRI, prostate-specific antigen density (PSAD), Prostate Health Index and urinary markers (Prostate Cancer Associated 3, SelectMdx™ and T2:ERG score) were assessed. Sensitivity (Se) and specificity (Sp) for each marker at their recommended cut-off for clinical practice were calculated. Comparison between diagnoses accuracy of each procedure and scenario was computed using mutual information based and direct effect contribution using a supervised Bayesian network approach. RESULTS: A mpMRI Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 showed higher Se than mpMRI PI-RADS score ≥4 for detection of PCa (82% vs 61%) and for the detection of ISUP grade >1 lesions (96% vs 80%). mpMRI PI-RADS score ≥3 performed better than a PSA level of ≥3 ng/mL (Se 96%, Sp 53% vs Se 91%, Sp 8%) for detection of clinically significant PCa. In case of negative mpMRI results, the supervised Bayesian network approach showed that urinary markers (with the same accuracy for all) and PSAD of ≥0.10 ng/mL/mL were the most useful indicators of decision to biopsy. CONCLUSIONS: We found that screening men at high genetic risk of PCa must be based on mpMRI without pre-screening based on a PSA level of >3 ng/mL, to avoid missing too many ISUP grade >1 tumours and to significantly reduce the number of unnecessary biopsies. However, urinary markers or a PSAD of ≥0.10 ng/mL/mL when mpMRI was negative increased the detection of ISUP grade >1 cancers. We suggest that a baseline mpMRI be discussed for men at high genetic risk from the age of 40 years.

Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

OBJECTIVE: To review the current status of germline and somatic (tumour) genetic testing for prostate cancer (PCa), and its relevance for clinical practice. METHODS: A narrative synthesis of various molecular profiles related to their clinical context was carried out. Current guidelines for genetic testing and its feasibility in clinical practice were analysed. We report the main identified genetic sequencing results or functional genomic scores for PCa published in the literature or obtained from the French PROGENE study. RESULTS: The molecular alterations observed in PCa are mostly linked to disruption of the androgen receptor (AR) pathway or DNA repair deficiency. The main known germline mutations affect the BReast CAncer gene 2 (BRCA2) and homeobox B13 (HOXB13) genes, whereas AR and tumour protein p53 (TP53) are the genes with most frequent somatic alterations in tumours from men with metastatic PCa. Molecular tests are now available for detecting some of these germline or somatic alterations and sometimes recommended by guidelines, but their utilisation must combine rationality and feasibility. They can guide specific therapies, notably for the management of metastatic disease. Indeed, following androgen deprivation, targeted therapies for PCa currently include poly-(ADP-ribose)-polymerase (PARP) inhibitors, immune checkpoint inhibitors, and prostate-specific membrane antigen (PSMA)-guided radiotherapy. The genetic tests currently approved for targeted therapies remain limited to the detection of BRCA1 and BRCA2 mutation and DNA mismatch repair deficiency, while large panels are recommended for germline analyses, not only for inherited cancer predisposing syndrome, but also for metastatic PCa. CONCLUSIONS: Further consensus aligning germline with somatic molecular analysis in metastatic PCa is required, including genomics scars, emergent immunohistochemistry, or functional pre-screen imaging. With rapid advances in knowledge and technology in the field, continuous updating of guidelines to help the clinical management of these individuals, and well-conducted studies to evaluate the benefits of genetic testing are needed.

Prognostic value of programmed death ligand-1 and programmed death-1 expression in patients with upper tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). RESULTS: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%]). CONCLUSIONS: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.

Eliciting men's preferences for decision-making relative to treatments of localized prostate cancer with a good or moderate prognosis.

PURPOSE: In diseases where there is no real consensus regarding treatment modalities, promoting shared decision-making can contribute to improving safety and quality of care. This is the case in low- or intermediate-risk localized prostate cancer (PC) treatment. The aim of this study was to investigate the preferences guiding men's decisions regarding the characteristics of the treatment strategies for PC to help physicians adopt a more patient-centered approach. METHODS: This prospective multicenter study used a discrete choice experiment (DCE). The attributes and the modalities were identified from a qualitative study and a literature review. Relative preferences were estimated using a logistic regression model. Interaction terms (demographic, clinical and socio-economic characteristics) were added to the model to assess heterogeneity in preferences. RESULTS: 652 men were enrolled in the study and completed a questionnaire with 12 pairs of hypothetical therapeutic alternatives between which they had to choose. Men's choices were significantly negatively influenced by the risk of impotence and urinary incontinence, death, and the length and frequency of care. They preferred treatments with a rescue possibility in case of deterioration or recurrence and the use of innovative technology. Surprisingly, the possibility of undergoing prostate ablation negatively influenced their choice. The results also highlighted differences in trade-offs according to socio-economic level. CONCLUSION: This study confirmed the importance of considering patients' preferences in the decision-making process. It appears essential to better understand these preferences to allow physicians to improve communication and promote case-by-case decision-making.

Endemic statistical paradoxes in epidemiologic studies distort knowledge on prostate cancer: mitigation and caution of fallacies in prostate cancer causal epidemiological studies.

PURPOSE OF REVIEW: Many studies on epidemiology of prostate cancer (PCa) are based on a diagnosis of PCa using PSA (prostate-specific antigen) level. However, biases can distort the interpretation of the results, which in turn limits policy and decision making on public health prevention strategies or clinical guidelines. The main confusion is to interpret the posterior probability of the outcome following the exposure as a change in the prevalence of the disease outcome, whereas this change reflects only the predictive values of the PSA test induced by the exposure of interest. RECENT FINDINGS: Many studies report potential causal factors involved in PCa risk. However, the lack of integration of how physiological changes in PSA values are associated with the exposures being investigated, they explain in part contradictory and controversial results on PCa risk factors in the literature. SUMMARY: A strategy to perform case--control studies based on PSA stratification is suggested to avoid misinterpretation related to PSA misclassification. Real data are analysed, and we show that we can exploit the mechanism of selection biases using different modalities of controls recruitment based on biomarker stratification to distinguish real from false causal factors.

Detection of urological cancers by the signature of organic volatile compounds in urine, from dogs to electronic noses.

PURPOSE OF REVIEW: Urine volatile organic compound (VOC) testing for early detection of urological cancers is a minimally invasive and promising method. The objective of this review was to present the results of recently published work on this subject. RECENT FINDINGS: Organic volatile compounds are produced through oxidative stress and peroxidation of cell membranes, and they are eliminated through feces, urine, and sweat. Studies looking for VOCs in urine for the diagnosis of urological cancers have mostly focused on bladder and prostate cancers. However, the number of patients included in the studies was small. The electronic nose was the most widely used means of detecting VOCs in urine for the detection of urological cancers. MOS sensors and pattern recognition machine learning were more used for the composition of electronic noses. Early detection of urological cancers by detection of VOCs in urine is a method with encouraging results with sensitivities ranging from 27 to 100% and specificities ranging from 72 to 94%. SUMMARY: The olfactory signature of urine from patients with urological cancers is a promising biomarker for the early diagnosis of urological cancers. The electronic nose with its ability to recognize complex odors is an excellent alterative to canine diagnosis and analytical techniques. Nevertheless, additional research improving the technology of Enoses and the methodology of the studies is necessary for its implementation in daily clinical practice.

DNA damage repair gene germline profiling for metastatic prostate cancer patients of different ancestries.

BACKGROUND: Germline and somatic mutations in DNA damage repair genes (DDRg) are now recognized as new biomarkers for the management of metastatic prostate cancers (mPC). We evaluate the frequency of germline DDRg mutations among French mPC patients of European and African ancestries. METHODS: Targeted next-generation sequencing of 21 DDRg was performed on germline DNA from 557 mPC patients, including 15.1% of cases with an African origin. RESULTS: Forty-seven germline mutations in 11 DDR genes were identified in 46 patients of the total cohort (8.3%). BRCA2 (4.1%) and ATM (2.0%) were the most frequently mutated genes. There was no difference in DDRg mutation frequency between mPC patients of European ancestry and those of African origin. Germline mutations of BRCA2 were associated with a positive family history of breast cancer (p = 0.02). The mean age at metastatic stage (59.7 vs. 67.0; p = 0.0003) and the mean age at death (65.2 vs. 73.9; p = 0.0003) were significantly earlier for carriers of BRCA2 mutation than for non-carriers. Moreover, the Cox model showed that BRCA2 positive status was statistically associated with poorer survival (hazard ratio: 0.29; 95% confidence interval 0.18-0.48; p < 0.0001). CONCLUSION: We showed that, in France, BRCA2 and ATM are the main predisposing DDR genes in mPC patients, with a particular aggressiveness for BRCA2 leading to early metastatic stage and death.

Impact of Renal Cell Carcinoma Histological Variants on Recurrence After Partial Nephrectomy: A Multi-Institutional, Prospective Study (UROCCR Study 82).

BACKGROUND: The prognostic impact of renal cell carcinoma (RCC) morphotype remains unclear in patients who undergo partial nephrectomy (PN). Our objective was to determine the risk factors for recurrence after PN, including RCC morphotype. METHODS: Patients with RCC who had undergone PN were extracted from the prospective, national French database, UroCCR. Patients with genetic predisposition, bilateral or multiple tumours, and those who had undergone secondary totalization were excluded. Primary endpoint was 5-year, recurrence-free survival (RFS), and secondary endpoint was overall survival (OS). Risk factors for recurrence were assessed by multivariable Cox regression analysis. RESULTS: Overall, 2,767 patients were included (70% male; median age: 61 years [interquartile range (IQR) 51-69]). Most (71.5%) of the PN procedures were robot-assisted. Overall, 2,573 (93.0%) patients were recurrence free, and 74 died (2.7%). Five-year RFS was 84.9% (IQR 82.4-87.4). A significant difference in RFS was observed between RCC morphotypes (p < 0.001). Surgical margins (hazard ratio [HR] = 2.0 [95% confidence interval (CI): 1.3-3.2], p < 0.01), pT stage >1 (HR = 2.6 [95% CI: 1.8-3.7], p < 0.01]) and Fuhrmann grade >2 (HR = 1.9 [95% CI: 1.4-2.6], p < 0.001) were risk factors for recurrence, whereas chromophobe subtype was a protective factor (HR = 0.08 [95% CI: 0.01-0.6], p = 0.02). Five-year OS was 94.0% [92.4-95.7], and there were no significant differences between RCC subgroups (p = 0.06). The main study limitation was its design (multicentre national database), which may be responsible for declarative bias. CONCLUSIONS: Chromophobe morphotype was significantly associated with better RFS in RCC patients who underwent PN. Conversely, pT stage, Fuhrman group and positive surgical margins were risk factors for recurrence.

Bladder carcinomas in patients with neurogenic bladder and urinary schistosomiasis: are they the same tumors?

PURPOSE: The aim of our study was to evaluate and compare the expression of different immunohistochemical markers in Bladder Carcinomas (BC) in patients with Neurogenic Bladder (NB) and Urinary Schistosomiasis (US) infection. MATERIALS AND METHODS: We collected tissue samples from patients with Neurogenic Bladder and Bladder Carcinoma (NBC Group) and from patients with Urinary Schistosomiasis infection and Bladder Carcinoma (SBC Group). We compared to these two groups to control samples from resection from patients with Urinary Schistosomiasis without Bladder Carcinoma (US Group); we also investigate patients' characteristics according to urothelial transitional cell carcinoma (TCC), and squamous cell carcinoma (SCC) histopathological differentiation. The expression of markers in all groups (CK7, CK14, CK20, FoxP3, GATA3, STAG2, CD3, CD8, Ki67, and P53) was analyzed using immunohistochemistry of tissue micro-array sections (TMA). RESULTS: Overall, 136 patients were included in the study (n = 72 in the NBC group, n = 33 in the SBC group, and n = 31 in the US group). In the TCC subgroup, the expression of CK7, CK14, CK20, and Ki67 was significantly higher compared to US controls (p 0.002; p < 0.001; p 0.036; p < 0.001). In the SCC subgroup, the expression of CK7, CK14, and CK20 was significantly higher compared to US controls (p 0.007; p < 0.001; p 0.005). Both in TCC and SCC subgroups, no difference in the expression of any tested markers was found comparing NBC and SBC groups. In US group, a significant higher expression of STAG2 was found compared to SCC subgroup (p 0.005). CONCLUSION: Based on our results, the profile of immunohistochemical biomarkers' expression in both NBC and SBC groups is similar.

Incidence of bladder cancer in neuro-urological patients in France: a nationwide study.

PURPOSE: The purpose of this study was to evaluate the incidence of bladder cancer (BCa) in patients with the main neurological diseases that induce neurogenic lower urinary tract dysfunction, namely, multiple sclerosis (MS), spinal cord injury (SCI) and spina bifida (SB). METHODS: We conducted a retrospective analysis of nationwide data from the French Hospital Discharge Database (PMSI) from January 2010 to December 2018. The incidence of BCa was calculated in patients with MS, SCI and SB. Incidence, sex, age, radical cystectomy after BCa diagnosis and in-hospital deaths were compared between the three groups. The Chi2 and Kruskal-Wallis tests were used for qualitative and quantitative data comparisons, respectively. RESULTS: Overall, 2015 neuro-urological patients (mean (± SD) age: 65.4 ± 12.3 years) were hospitalized in France between 2010 and 2018 with a new diagnosis of BCa. In neuro-urological patients, BCa was more frequent in men than in women (sex ratio: 3.08). The incidence of BCa in neuro-urological patients was 174.9/100,000 persons/year. The incidence of BCa was 791.1/100,000 persons/year in SCI compared to 56.6 in MS and 113.8 in SB (p < 0.0001). After the initial diagnosis of BCa, 551 (27.3%) patients underwent a radical cystectomy and 613 (30.4%) died in hospital after BCa diagnosis. CONCLUSIONS: The incidence of BCa in France between 2010 and 2018 was 174.9/100 000 persons/year, and was particularly high in patients with SCI.

A study of the immunohistochemical profile of bladder cancer in neuro-urological patients by the French Association of Urology.

PURPOSE: To establish whether the expression of markers of cell differentiation (CK7, CK14, CK20, GATA3), apoptosis (p53), proliferation (Ki67, STAG2) and peri-tumoural lymphocytes (CD3, CD8), provides specific information about urothelial carcinogenesis in neuro-urological patients with bladder cancer (NBC). METHODS: Tissue samples from NBC were retrieved from 15 centres in France and compared to control samples from non neuro-urological patients with bladder cancer (NNBC) and from neuro-urological patients without bladder cancer (NB). The expression of CK7, CK14, CK20, GATA3, p53, Ki67, STAG2, CD3 and CD8 markers was analysed using immunohistochemistry of tissue microarray sections. RESULTS: Overall, tissue samples from 124 patients were included in the study (n = 72 NBC, n = 26 NNBC and n = 26 NB). Muscle invasive bladder cancer (MIBC) was found in 52 NBC patients (72.2%) and squamous cell differentiation in 9 (12.5%). In NBC samples, the expression of CK20 and GATA3 was significantly more frequent in NMIBC compared to MIBC (p = 0.015 and p = 0.004, respectively). CK20 and GATA3 were significantly more expressed in NBC compared to NNBC (p < 0.001 and p = 0.010, respectively). The expression of CK14, Ki67, CD3 and CD8 was significantly more frequent in NBC than in NNBC samples (p = 0.005, p < 0.001, p < 0.001 and p < 0.001, respectively). The expression of CD3 and CD8 was similar in NBC and NB samples. CONCLUSION: In NBC, markers of basal differentiation, proliferation and peri-tumoural lymphocytes were significantly more expressed compared to NNBC controls. These results suggest the aggressiveness of NBC and the role of chronic inflammation in the carcinogenesis of bladder cancer in neuro-urological patients.

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

Bayesian predictive model to assess BRCA2 mutational status according to clinical history: Early onset, metastatic phenotype or family history of breast/ovary cancer.

BACKGROUND: Mutations of the BRCA2 gene are the most frequent alterations found in germline DNA from men with prostate cancer (PrCa), but clinical parameters that could better orientate for BRCA2 mutation screening need to be established. METHODS: Germline DNA from 325 PrCa patients (median age at diagnosis: 57 years old) was screened for BRCA2 mutation. The mutation frequency was compared between three subgroups: patients with an age at diagnosis at 55 years old and under (Group I); a personal or family history of breast, uterine or ovarian cancer (Group II); or a metastatic disease (Group III). Frequency of BRCA2 mutations was established for each combination of phenotypes, and compared between patients meeting or not the criteria for each subgroup using Fisher's exact test. Mutual information, direct effect, elasticity and contribution to the mutational status of each phenotype, taking into account overlap between subgroups, were also estimated using Bayesian algorithms. RESULTS: The proportion of BRCA2 mutation was 5.9% in Group I, 10.9% in Group II and 6.9% in Group III. The frequency of BRCA2 mutation was significantly higher among patients of Group II (p = .006), and reached 15.6% among patients of this group who presented a metastatic disease. Mutual information, direct effect, elasticity and contribution to the mutational status were the highest for phenotype II. Fifteen (71.4%) of the 21 BRCA2 mutation carriers had an aggressive form of the disease. Four (19%) of them died from PrCa after a median follow-up duration of 64.5 months. CONCLUSIONS: Our results showed that a higher frequency of BRCA2 mutation carriers is observed, not only among PrCa patients with young onset or a metastatic disease, but also with a personal or a familial history of breast cancer.

Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer.

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.

Genetic variability in 13q33 and 9q34 is linked to aggressiveness patterns and a higher risk of progression of non-muscle-invasive bladder cancer at the time of diagnosis.

OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with patterns of aggressiveness of non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: From January 2011 to December 2018, 476 patients with NMIBC were prospectively included. The first step aimed to identify SNPs associated with aggressiveness patterns (e.g. ≥pT1or high-grade/Grade 3 or presence of carcinoma in situ) by analysing the data of a genome-wide association study (GWAS) on 165 patients with BC. The second step aimed to validate the SNPs previously identified, by genotyping the germline DNA of 311 patients with NMIBC. RESULTS: Overall, the median (interquartile range) age was 66 (58-75) years and the rate of patients with aggressive NMIBC was comparable between both groups (46% vs 46%, P = 1). GWAS data analysis identified four SNPs associated with an aggressive NMIBC (rs12615669, rs4976845, rs2989734, and rs2802288). In the validation cohort, the genotype CC of rs12615669, as well as age >70 years at the time of diagnosis were associated with aggressive NMIBC (P = 0.008 and P < 0.001, respectively). Genotyping of the entire cohort showed an association between aggressive NMIBC and the T allele of rs12615669 (P = 0.0007), the A allele of rs4976845 (P = 0.012), and the A allele of rs2989734 (P = 0.007). A significant association was also found for the entire cohort between the risk of progression and the A allele of rs4976845 (P = 0.04). CONCLUSION: This two-phase study identified three SNPs (rs12615669, rs4976845, and rs2989734) associated with aggressive NMIBC and one SNP (rs4976845) associated with a higher risk of progression.

PD-L1 (SP142) testing is concordant between Benchmark Ultra and Bond-III stainers.

BACKGROUND: Atezolizumab is an inhibitor of programmed death-ligand 1 (PD-L1), used to treat advanced or metastatic bladder cancer, and in trials for non-invasive disease. In order to be eligible for treatment, patients require a PD-L1 immune cell score ≥ 5%, using the Ventana SP142 PD-L1 assay. Many laboratories do not have access to the required Ventana Benchmark Ultra stainer, and it is unclear if the assay performs similarly on other stainers. In this study, we compare SP142 assay results between Ventana Benchmark Ultra and Leica Bond-III stainers. METHODS: Serial sections of 90 samples of transurethral bladder resections (comprising 51 pTaHG, 8 pTis, 18 pT1, 10 pT2 tumors) were stained using the SP142 PD-L1 antibody on Ventana Benchmark Ultra and Leica Bond-III stainers, manually scored, and compared using accuracy and Cohen's kappa measures. RESULTS: Both devices yielded highly concordant PD-L1 immune cell scores (accuracy 0.84, Cohen's κ 0.732). Moreover, we found similar tumor cell (TC) PD-L1 scores using both stainers, and a trend towards greater TC scores in pT2 stage samples (p = 0.05). CONCLUSION: This study is the first to compare the SP142 antibody in bladder cancer on two different stainers. Our results indicate that both Benchmark Ultra and Bond-III stainers yield highly concordant results using the SP142 PD-L1 antibody.

Pathological reporting of cystectomy lymph nodes: a retrospective analysis of experience in Paris.

PURPOSE: Pathological evaluation of pelvic lymph node (LN) dissection (PLND) is important for management of cystectomy patients. However, challenges such as unclear interobserver variability of LN counting remain. Here, we assess interobserver variability of LN measures and their clinical utility, with a focus on variant histology. METHODS: We retrieved radical cystectomy cases with PLND between 2010 and 2016 and reevaluated pathological parameters; number of total and metastatic LN, LN density (LND), length of metastatic LN and metastases, extranodal extension (ENE). RESULTS: We report 96 patients: median age of 71a, 34 cases pN+, 36 cases with any extent of variant histology, median follow-up 10 months. Perivesical LN were only rarely identified, but frequently metastatic (4/9). Variant histology (34 cases) frequently exhibited LN metastasis (53% of pN+ cases). Interobserver variance was poor for total LN (kappa = 0.167), excellent for positive LN (0.85) and pN staging (0.96), and mediocre for LND (0.53). ROC analysis suggests that both LND and the sum of LN metastasis length may predict outcome (AUC 0.83 and 0.75, respectively). CONCLUSION: Our study confirms the notion of LND as a prognostic measure, but cautions due to strong interobserver variance of LN counts. The sum length of LN metastases could be a measure that is independent of LN counts. We find that microscopically identified perivesical LN merit particular attention. In summary, our study highlights current challenges in pathological reporting of PLND, confirms previous observations and forms a basis for further studies.