Publications by authors named "Sita H Vermeulen"

100 Publications

Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non-muscle-invasive Bladder Cancer.

Eur Urol Oncol 2021 Aug 2. Epub 2021 Aug 2.

Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands.

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed.

Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC.

Design, Setting, And Participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation.

Outcome Measurements And Statistical Analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort.

Results And Limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p = 0.003). Twelve other loci were suggestively associated with RFS (p < 10), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature.

Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression.

Patient Summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.
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http://dx.doi.org/10.1016/j.euo.2021.07.001DOI Listing
August 2021

Lysine methyltransferase G9a is an important modulator of trained immunity.

Clin Transl Immunology 2021 18;10(2):e1253. Epub 2021 Feb 18.

Department of Internal Medicine Radboud Center for Infectious Diseases (RCI) Radboud University Medical Center Nijmegen The Netherlands.

Objectives: Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a innate immune memory, and its effects in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guérin (BCG).

Methods: EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX-01294 was used to investigate the effect on trained immunity responses . Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP-qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX-01294-treated monocytes .

Results: The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX-01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands . This was accompanied by decreased H3K9me2 at the promoters of pro-inflammatory genes. G9a inhibition was also associated with amplified trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro-inflammatory genes.

Conclusion: Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients.
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http://dx.doi.org/10.1002/cti2.1253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890679PMC
February 2021

Analysis of Drug Metabolizing Gene Panel in Osteosarcoma Patients Identifies Association Between Variants in and and Methotrexate Levels and Toxicities.

Front Pharmacol 2020 12;11:1241. Epub 2020 Aug 12.

Department of Pediatrics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5'-untranslated region of  was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 - -0.167); p = 2.60 × 10]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in  {rs4803418 [coef -0.187 (95% CI -0.275 - -0.099); p = 3.04 × 10] and rs4803419 [coef -0.186 (95% CI -0.278 - -0.093); p = 8.80 × 10]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in  [coef 0.193 (95% CI 0.099 - 0.287); p = 6.02 × 10]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in , and to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.
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http://dx.doi.org/10.3389/fphar.2020.01241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435008PMC
August 2020

Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer.

Nat Rev Urol 2020 Sep 16;17(9):513-525. Epub 2020 Jul 16.

Department for Health Evidence, Radboud University Medical Center, Radboud Institute for Health Sciences (RIHS), Nijmegen, Netherlands.

Intravesical BCG instillation is the gold-standard adjuvant immunotherapy for patients with high-risk non-muscle-invasive bladder cancer. However, the precise mechanism of action by which BCG asserts its beneficial effects is still unclear. BCG has been shown to induce a non-specific enhancement of the biological function in cells of the innate immune system, creating a de facto heterologous immunological memory that has been termed trained immunity. Trained immunity or innate immune memory enables innate immune cells to mount a more robust response to secondary non-related stimuli after being initially primed (or trained) by a challenge such as BCG. BCG-induced trained immunity is characterized by the metabolic rewiring of monocyte intracellular metabolism and epigenetic modifications, which subsequently lead to functional reprogramming effects, such as an increased production of cytokines, on restimulation. Results from BCG vaccination studies in humans show that trained immunity might at least partly account for the heterologous beneficial effects of BCG vaccination. Additionally, immunity might have a role in the effect of BCG immunotherapy for bladder cancer. Based on these indications, we propose that trained immunity could be one of the important mechanisms mediating BCG immunotherapy and could provide a basis for further improvements towards a personalized approach to BCG therapy in non-muscle-invasive bladder cancer.
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http://dx.doi.org/10.1038/s41585-020-0346-4DOI Listing
September 2020

Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

PLoS One 2019 28;14(5):e0217477. Epub 2019 May 28.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Introduction: Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.

Methods: We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing.

Results: When we applied a MAF of ≥1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing.

Conclusion: Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538182PMC
January 2020

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Genotype-Guided Thiopurine Dosing Does not Lead to Additional Costs in Patients With Inflammatory Bowel Disease.

J Crohns Colitis 2019 Jul;13(7):838-845

Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background And Aims: Decreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life.

Methods: An a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications.

Results: The intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were €52 per patient [95% percentiles -682, 569]. Mean incremental QALYs were 0.001 [95% percentiles -0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss.

Conclusions: Genotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.
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http://dx.doi.org/10.1093/ecco-jcc/jjz009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142326PMC
July 2019

Identification of an enhancer region within the TP63/LEPREL1 locus containing genetic variants associated with bladder cancer risk.

Cell Oncol (Dordr) 2018 Oct 28;41(5):555-568. Epub 2018 Jun 28.

Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.

Purpose: Genome-wide association studies (GWAS) have led to the identification of a bladder cancer susceptibility variant (rs710521) in a non-coding intergenic region between the TP63 and LEPREL1 genes on chromosome 3q28, suggesting a role in the transcriptional regulation of these genes. In this study, we aimed to functionally characterize the 3q28 bladder cancer risk locus.

Methods: Fine-mapping was performed by focusing on the region surrounding rs710521, and variants were prioritized for further experiments using ENCODE regulatory data. The enhancer activity of the identified region was evaluated using dual-luciferase assays. CRISPR/Cas9-mediated deletion of the enhancer region was performed and the effect of this deletion on cell proliferation and gene expression levels was evaluated using CellTiter-Glo and RT-qPCR, respectively.

Results: Fine-mapping of the GWAS signal region led to the identification of twenty SNPs that showed a stronger association with bladder cancer risk than rs710521. Using publicly available data on regulatory elements and sequences, an enhancer region containing the bladder cancer risk variants was identified. Through reporter assays, we found that the presence of the enhancer region significantly increased ΔNTP63 promoter activity in bladder cancer-derived cell lines. CRISPR/Cas9-mediated deletion of the enhancer region reduced the viability of bladder cancer cells by decreasing the expression of ΔNTP63 and p63 target genes.

Conclusions: Taken together, our data show that bladder cancer risk-associated variants on chromosome 3q28 are located in an active enhancer region. Further characterization of the allele-specific activity of the identified enhancer and its target genes may lead to the identification of novel signaling pathways involved in bladder carcinogenesis.
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http://dx.doi.org/10.1007/s13402-018-0393-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153957PMC
October 2018

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

J Natl Cancer Inst 2018 09;110(9):967-974

Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population.

Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database.

Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele.

Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.
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http://dx.doi.org/10.1093/jnci/djy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924PMC
September 2018

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.

Drug Alcohol Depend 2018 07 25;188:94-101. Epub 2018 Apr 25.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.

Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.

Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10) and rs8034191 (p = 6.31 × 10) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.

Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.03.026DOI Listing
July 2018

Smoking intensity and bladder cancer aggressiveness at diagnosis.

PLoS One 2018 23;13(3):e0194039. Epub 2018 Mar 23.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Objective: To explore the relation between cigarette smoking intensity and bladder cancer aggressiveness at first diagnosis.

Methods: Patients diagnosed with urinary bladder cancer (BC) between 1995-2011 under the age of 75 years were retrospectively identified from the Netherlands Cancer Registry and invited for a study on genetic and lifestyle risk factors for BC. Information on patients' self-reported smoking history was retrieved by means of a postal questionnaire. Tumors were stratified regarding the risk of progression defined by tumor stage and grade. Multinomial logistic regression was used to analyze the relation between smoking intensity and aggressiveness of the tumor.

Results: The UBC study population comprised 323 (17.4%) never smokers, 870 (46.8%) former cigarette smokers, and 630 (33.9%) current cigarette smokers. A higher smoking amount was a risk factor of getting high-risk non-muscle invasive bladder cancer (NMIBC) compared with low-risk NMIBC in ever and former cigarette smokers (OR: 1.02 per cigarette smoked, 95% CI: 1.00-1.03 and OR: 1.03, 95% CI: 1.01-1.05, respectively). A statistically significant dose-response increase in the risk of a more aggressive cancer type (high-risk NMIBC and MIBC) was observed with increasing smoking duration among former smokers (p for trend 0.035 and 0.008, respectively). No significant association of the evaluated smoking intensity variables was observed in current smokers. A longer time of smoking cessation correlated with a lower odds of a more aggressive cancer.

Conclusion: We observed a weak increase in the risk of a more aggressive tumor type with increasing smoking intensity in former smokers, but this association was absent in current smokers. This conflicting result may suggest that there is no strong relation between smoking intensity and bladder cancer aggressiveness. Analyses of prospective studies with longitudinal smoking assessment may provide a more definitive answer to the research question.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865728PMC
June 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

A Genetic Polymorphism in Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma.

Clin Cancer Res 2018 05 28;24(10):2350-2356. Epub 2018 Feb 28.

Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.

The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. Twenty-seven single-nucleotide polymorphisms (SNP) in (PD-L1), (PD-1), and were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association ( < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. rs231775 and rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72-0.98; = 0.028, and HR, 0.73; 95% CI, 0.54-0.99; = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of < 0.05. After meta-analysis, rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72-0.95; = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found. The G-allele of rs231775 in the gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2815DOI Listing
May 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Nat Commun 2017 10 13;8(1):910. Epub 2017 Oct 13.

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
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http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer.

Carcinogenesis 2017 12;38(12):1167-1179

Systems Toxicology, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Germany.

Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93-3.47; P = 1.87 × 10-10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10-2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers.
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http://dx.doi.org/10.1093/carcin/bgx102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862341PMC
December 2017

Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life.

Am J Hum Genet 2017 Jul 29;101(1):50-64. Epub 2017 Jun 29.

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address:

Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.
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http://dx.doi.org/10.1016/j.ajhg.2017.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501773PMC
July 2017

Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity.

Urol Oncol 2017 08 3;35(8):529.e9-529.e16. Epub 2017 Apr 3.

Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Objective: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort.

Methods And Materials: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses.

Results: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy.

Conclusions: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available.
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http://dx.doi.org/10.1016/j.urolonc.2017.03.009DOI Listing
August 2017

Genetic variants associated with type 2 diabetes and adiposity and risk of intracranial and abdominal aortic aneurysms.

Eur J Hum Genet 2017 06 5;25(6):758-762. Epub 2017 Apr 5.

Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Epidemiological studies show that type 2 diabetes (T2D) is inversely associated with intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Although adiposity has not been considered a risk factor for IA, there have been inconsistent reports relating adiposity to AAA risk. We assessed whether these observations have a genetic, causal basis. To this end, we extracted genotypes of validated single-nucleotide polymorphisms associated with T2D (n=65), body mass index (BMI) (n=97) and waist-hip ratio adjusted for BMI (WHRadjBMI) (n=47) from genotype data collected in 717 IA cases and 1988 controls, and in 818 AAA cases and 3004 controls, all of Dutch descent. For each of these three traits, we computed genetic risk scores (GRS) for each individual in these case-control data sets by summing the number of risk alleles weighted by their published effect size, and tested whether these GRS were associated with risk of aneurysm. We divided the cohorts into GRS quartiles, and compared IA and AAA risk in the highest with the lowest GRS quartile using logistic regression. We found no evidence for association in IA or AAA risk between top and bottom quartiles for the genetic risk scores for T2D, BMI and WHRadjBMI. However, additional Mendelian randomization analyses suggested a trend to potentially causal associations between BMI and WHRadjBMI and risk of AAA. Overall, our results do not support epidemiological observations relating T2D to aneurysm risk, but may indicate a potential role of adiposity in AAA that requires further investigation.
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http://dx.doi.org/10.1038/ejhg.2017.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477373PMC
June 2017

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

JAMA Oncol 2017 May;3(5):636-651

Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction And Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes And Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions And Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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http://dx.doi.org/10.1001/jamaoncol.2016.5945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638008PMC
May 2017

Rare and low-frequency coding variants alter human adult height.

Nature 2017 02 1;542(7640):186-190. Epub 2017 Feb 1.

Netherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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http://dx.doi.org/10.1038/nature21039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302847PMC
February 2017

Cohort Profile: The Nijmegen Biomedical Study (NBS).

Int J Epidemiol 2017 08;46(4):1099-1100j

Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1093/ije/dyw268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837647PMC
August 2017

Meta-GWAS and Meta-Analysis of Exome Array Studies Do Not Reveal Genetic Determinants of Serum Hepcidin.

PLoS One 2016 15;11(11):e0166628. Epub 2016 Nov 15.

Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166628PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112847PMC
June 2017

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

J Am Heart Assoc 2016 07 14;5(7). Epub 2016 Jul 14.

Surgery Department, University of Otago, Dunedin, New Zealand.

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.

Methods And Results: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)).

Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
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http://dx.doi.org/10.1161/JAHA.115.002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015357PMC
July 2016

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.

J Crohns Colitis 2017 Feb 9;11(2):175-184. Epub 2016 Jul 9.

Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.

Background And Aims: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment.

Methods: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 10/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial.

Results: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 10 erythrocytes and 3525 pmol/8 × 10 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]).

Conclusions: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.
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http://dx.doi.org/10.1093/ecco-jcc/jjw130DOI Listing
February 2017

Independent Replication of Published Germline Polymorphisms Associated with Urinary Bladder Cancer Prognosis and Treatment Response.

Bladder Cancer 2016 Jan 7;2(1):77-89. Epub 2016 Jan 7.

Radboud University Medical Center, Radboud Institute for Health Sciences , Nijmegen, The Netherlands.

Background: Many studies investigated the prognostic or predictive relevance of single nucleotide polymorphisms (SNPs) in biologically plausible genes in urinary bladder cancer (UBC) patients. Most published SNP associations have never been replicated in independent patient series.

Objective: To independently replicate all previously reported associations between germline SNPs and disease prognosis or treatment response in UBC.

Methods: A Pubmed search was performed to identify studies published by July 1, 2014 reporting on germline SNP associations with UBC prognosis or treatment response. For the replication series, consisting of 1,284 non-muscle-invasive bladder cancer (NMIBC) and 275 muscle-invasive or metastatic bladder cancer (MIBC) patients recruited through the Netherlands Cancer Registry, detailed clinical data were retrieved from medical charts. Patients were genotyped using a genome-wide SNP array. SNP association with recurrence-free, progression-free, and overall survival (OS) within specific patient and treatment strata was tested using Cox regression analyses.

Results: For only six of the 114 evaluated SNPs, the association with either UBC prognosis or treatment response was replicated at the  <  0.05 level: rs1799793 () and rs187238 () for BCG recurrence; rs6678136 () and rs11585883 () for NMIBC progression; rs12035879 () and rs2075786 () for MIBC OS.

Conclusions: Non-replicated genetic associations in the literature require cautious interpretation. This single replication does not provide definitive proof of association for the six SNPs, and non-replication of other SNPs may result from population-specific effects or the retrospective patient enrollment.
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http://dx.doi.org/10.3233/BLC-150027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927992PMC
January 2016

The clinical phenotype of hereditary versus sporadic prostate cancer: HPC definition revisited.

Prostate 2016 07 14;76(10):897-904. Epub 2016 Mar 14.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Background: The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC).

Methods: HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n = 324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population-based study into the genetic susceptibility of PC (n = 1,664). Detailed clinical data were collected by NCR-registrars, using a standardized registration form. Follow-up extended up to the end of 2013. Differences between the groups were evaluated by cross-tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression-free and overall survival were evaluated using χ(2) testing with GEE in a proportional-hazards model.

Results: HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high-risk disease (NICE-criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan-Meier 5-year progression-free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P = 0.30). The 5-year overall survival was 85% (95%CI 81-89%) for HPC versus 80% (95%CI 78-82%) for SPC (P = 0.03).

Conclusions: HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics-based definition of HPC, which may lead to over-diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re-evaluated, aiming at a reduction of over-diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897-904, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pros.23179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069637PMC
July 2016
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