Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma.

Introduction: Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment.

Novel loci and biomedical consequences of iron homoeostasis variation.

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported.

Experience of urologists, oncologists and nurse practitioners with mainstream genetic testing in metastatic prostate cancer.

Background: International guidelines recommend germline genetic testing for men with metastatic prostate cancer. If offered to all patients by genetic healthcare professionals, there will be insufficient capacity to cope with the high patient numbers. In a mainstreaming pathway, non-genetic healthcare professionals (ngHCPs) discuss and order germline genetic testing instead of referring patients to genetic healthcare professionals.

The impact of positive surgical margins after cystectomy on oncological outcomes: a nationwide study.

Objective: To evaluate whether surgical margin status, alongside existing postoperative risk indicators, improves the identification of bladder cancer patients who may benefit from adjuvant therapy following radical cystectomy (RC).

Methods: In this nationwide cohort study, patients aged ≥18 years diagnosed with muscle-invasive bladder cancer (MIBC) without nodal or distant metastasis (cT2-4aN0/xM0) between November 2017 and December 2020 who underwent RC were selected from the Netherlands Cancer Registry. Detailed information on surgical margin status was obtained through linkage with the Dutch central pathology database, Palga.

Associations of physical activity and sedentary time with health-related quality of life in patients with localized renal cell cancer: a cross-sectional analysis within the ReLife study.

Purpose: This study examined the associations of device-measured moderate-to-vigorous physical activity (MVPA) and sedentary time as well as self-reported MVPA with health-related quality of life (HRQoL) in patients with localized renal cell cancer (RCC) in the recovery phase after surgery.

Methods: At 3 months post-surgery, 341 patients with stage I-III RCC participating in the ReLife study wore an ActivPAL3 device to determine MVPA and sedentary time. The SQUASH questionnaire was used for assessing self-reported MVPA, and the EORTC QLQ-C30 for assessing HRQoL (range 0-100).

Smoking behavior and the risks of tumor recurrence and progression in patients with non-muscle-invasive bladder cancer.

Studies on the relationship of cigarette smoking with the risks of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are inconsistent and prospective data are scarce. Therefore, we aimed to assess the association of smoking behavior with risks of NMIBC recurrence and progression. We used data of the prospective multi-center cohort study UroLife, including 1495 patients with NMIBC who reported information on smoking at 6 weeks post-diagnosis (baseline; reflecting present and pre-diagnosis).

Lifestyle Advice to Patients with Bladder Cancer: A National Survey of Dutch Urologists.

Background: Not much is known about the extent to which urologists discuss lifestyle with patients with bladder cancer (BC), despite patients considering urologists as an important source of information and motivation.

Objective: To determine how often lifestyle is asked about, advised on, and referred for by Dutch urologists to patients with BC, as well as to evaluate urologists' perceptions and barriers.

Methods: An anonymous online survey was sent to Dutch urologists.

Risk of Progression of High-grade Primary T1 Non-muscle-invasive Bladder cancer in a Contemporary Cohort.

Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) receive bacillus Calmette-Guérin (BCG) instillations to reduce the risk of progression. For patients with very high-risk NMIBC, immediate radical cystectomy may be considered, as patients who experience disease progression despite BCG treatment have a worse prognosis. However, guideline-recommended stratification for the risk of progression is based on data from patients who were not exposed to BCG.

Hereditary and Familial Traits in Urological Cancers and Their Underlying Genes.

Unlabelled: Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Aims: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10).

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives.

Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives' medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives.

Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project.

In this cohort profile article we describe the lifetime major depressive disorder (MDD) database that has been established as part of the BIObanks Netherlands Internet Collaboration (BIONIC). Across the Netherlands we collected data on () lifetime MDD diagnosis in 132,850 Dutch individuals. Currently, = 66,684 of these also have genomewide single nucleotide polymorphism (SNP) data.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.

Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.

Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.

Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Unlabelled: Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated.

Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established.

Genetic relationship between the immune system and autism.

Autism spectrum disorder (ASD) is a common and complex neurodevelopmental condition. The pathophysiology of ASD is poorly defined; however, it includes a strong genetic component and there is increasing evidence to support a role of immune dysregulation. Nonetheless, it is unclear which immune phenotypes link to ASD through genetics.

Health-related Quality of Life During the First 4 Years After Non-Muscle-invasive Bladder Cancer Diagnosis: Results of a Large Multicentre Prospective Cohort.

Background: The health-related quality of life (HRQoL) of patients with non-muscle-invasive bladder cancer (NMIBC) may be impaired due to the chronic and burdensome disease course, but longitudinal data are limited.

Objective: To evaluate HRQoL outcomes during the first 4 yr after NMIBC diagnosis, and to compare HRQoL across patient characteristics and with a normative population.

Design, Setting, And Participants: Patients with NMIBC (n = 1019) were included from the multicentre prospective cohort UroLife.