Genome-wide association study for tumour stage, grade, size, and age at diagnosis of non-muscle-invasive bladder cancer

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade. OBJECTIVE: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables). RESULTS AND LIMITATIONS: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ss=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis. CONCLUSIONS: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding. PATIENT SUMMARY: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity

The present and future burden of urinary bladder cancer in the world

Urinary bladder cancer (UBC) is a common disease worldwide. At any point in time 2.7 million people have a history of UBC. The incidence of UBC varies over the world with highest rates in developed communities. But the burden of UBC will increase in less developed areas of the world. These changes can be attributed to global changes in exposure to risk factors for UBC and growth and aging of the world population

Urologists’ and GPs’ knowledge of hereditary prostate cancer is suboptimal for prostate cancer counseling: a nation-wide survey in The Netherlands

A family history of prostate cancer (PCa) is an established risk factor for PCa. In case of a positive family history, the balance between positive and adverse effects of prostate-specific antigen (PSA) testing might be different from the general population, for which the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a beneficial effect on mortality. This, however, went at the cost of considerable overtreatment. This study assessed Dutch physicians’ knowledge of heredity and PCa and their ‘post-ERSPC’ attitude towards PCa testing, including consideration of family history. In January 2010, all Dutch urologists and clinical geneticists (CGs) and 300 general practitioners (GPs) were invited by email to complete an anonymous online survey, which contained questions about hereditary PCa and their attitudes towards PCa case-finding and screening. 109 urologists (31%), 69 GPs (23%) and 46 CGs (31%) completed the survey. CGs had the most accurate knowledge of hereditary PCa. All but 1 CG mentioned at least one inherited trait with PCa, compared to only 25% of urologists and 9% of GPs. CGs hardly ever counseled men about PCa testing. Most urologists and GPs discuss possible risks and benefits before testing for PCa with PSA. Remarkably, 35–40% of them do not take family history into consideration. Knowledge of urologists and GPs about heredity and PCa is suboptimal. Hence, PCa counseling might not be optimal for men with a positive family history. Multidisciplinary guidelines on this topic should be developed to optimize personalized counseling

Hospital volume is associated with postoperative mortality after radical cystectomy for treatment of bladder cancer

Contains fulltext : 237666.pdf (Publisher’s version ) (Open Access)OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered

Urine cell-based DNA methylation classifier for monitoring bladder cancer

Background: Current standard methods used to detect and monitor bladder cancer (BC) are invasive or have low sensitivity. This study aimed to develop a urine methylation biomarker classifier for BC monitoring and validate this classifier in patients in follow-up for bladder cancer (PFBC). Methods: Voided urine samples (N = 725) from BC patients, controls, and PFBC were prospectively collected in four centers. Finally, 626 urine samples were available for analysis. DNA was extracted from the urinary cells and bisulfite modificated, and methylation status was analyzed using pyrosequencing. Cytology was available from a subset of patients (N = 399). In the discovery phase, seven selected genes from the literature (CDH13, CFTR, NID2, SALL3, TMEFF2, TWIST1, and VIM2) were studied in 111 BC and 57 control samples. This training set was used to develop a gene classifier by logistic regression and was validated in 458 PFBC samples (173 with recurrence). Results: A three-gene methylation classifier containing CFTR, SALL3, and TWIST1 was developed in the training set (AUC 0.874). The classifier achieved an AUC of 0.741 in the validation series. Cytology results were available for 308 samples from the validation set. Cytology achieved AUC 0.696 whereas the classifier in this subset of patients reached an AUC 0.768. Combining the methylation classifier with cytology results achieved an AUC 0.86 in the validation set, with a sensitivity of 96%, a specificity of 40%, and a positive and negative predictive value of 56 and 92%, respectively. Conclusions: The combination of the three-gene methylation classifier and cytology results has high sensitivity and high negative predictive value in a real clinical scenario (PFBC). The proposed classifier is a useful test for predicting BC recurrence and decrease the number of cystoscopies in the follow-up of BC patients. If only patients with a positive combined classifier result would be cystoscopied, 36% of all cystoscopies can be prevented

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect

[Abstract] Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. Methods: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. Results: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. Conclusions: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints

Sequence variant at 4q25 near PITX2 associates with appendicitis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAppendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10(-11)). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk

Association of Risk Variants in the <i>CFH </i>Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.</p

Prognostic relevance of number and bilaterality of positive surgical margins after radical prostatectomy

Item does not contain fulltextPURPOSE: Positive surgical margin (PSM) status following radical prostatectomy (RP) is a well-established prognostic factor. The aim of the present study is to evaluate whether number of PSMs or bilaterality of PSMs might have prognostic significance for biochemical recurrence (BCR) in the population with a PSM status following RP. METHODS: We evaluated 1,395 RP pathology reports from our center between 1980 and 2006. All patients who underwent (neo)-adjuvant therapy were excluded, leaving a cohort of 1,009 patients, with 249 (24.7%) subjects having a PSM at RP of whom 29.4% had multiple PSMs (>/= 2 sites), while 13.6% had bilateral PSMs. Median follow-up was 40 months (range 0-258 months). We used BCR-free survival as the primary study outcome. BCR was defined as any rise in PSA above or equal to 0.2 ng/ml. RESULTS: Of patients with a PSM status, 41% (95% CI: 33-49%) developed BCR within 5 years, compared to 12% (95% CI: 9-15%) in the population without a PSM. Multivariable analysis identified PSA at diagnosis and RP Gleason score as independent predictive factors for BCR. Increasing number and/or bilaterality of PSM did not lead to significant higher rates of BCR. CONCLUSION: In patients with a PSM, the number of positive sites or bilaterality of PSM status does not add prognostic information for risk of BCR. Survival curve slopes were different for patients with bilateral PSM, showing a significant tendency to progress to BCR earlier during follow-up than patients with unilateral PSM.1 februari 201