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Simple Summary: We were motivated by the need to improve early detection of bladder cancer (BLCA). Our aim was to uncover genetic alterations within the bladder's lining, called urothelium, where BLCA starts. We examined normal tissue margins near and far away from tumors, studying the abnormalities that may predispose to BLCA. Recognizing the post-zygotic variability in bladder urothelium resulting from exposure to carcinogens in urine, our novel approach examined up to eight fragments of normal epithelium from each individual. Using a sensitive computational method, we successfully identified novel, but also well-known cancer-related regions across normal samples, confirming the efficacy of our methodology. Additionally, we provide further evidence for the already recognized connection between the loss of chromosome Y in men and BLCA. This positions our method for broader use in larger cohorts and different cancer types. Looking ahead, our methodology holds promise for identifying biomarkers that predict BLCA in analysis of urine. Bladder urothelial carcinoma (BLCA) is the 10th most common cancer with a low survival rate and strong male bias. We studied the field cancerization in BLCA using multi-sample- and multi-tissue-per-patient protocol for sensitive detection of autosomal post-zygotic chromosomal alterations and loss of chromosome Y (LOY). We analysed 277 samples of histologically normal urothelium, 145 tumors and 63 blood samples from 52 males and 15 females, using the in-house adapted Mosaic Chromosomal Alterations (MoChA) pipeline. This approach allows identification of the early aberrations in urothelium from BLCA patients. Overall, 45% of patients exhibited at least one alteration in at least one normal urothelium sample. Recurrence analysis resulted in 16 hotspots composed of either gains and copy number neutral loss of heterozygosity (CN-LOH) or deletions and CN-LOH, encompassing well-known and new BLCA cancer driver genes. Conservative assessment of LOY showed 29%, 27% and 18% of LOY-cells in tumors, blood and normal urothelium, respectively. We provide a proof of principle that our approach can characterize the earliest alterations preconditioning normal urothelium to BLCA development. Frequent LOY in blood and urothelium-derived tissues suggest its involvement in BLCA. [ABSTRACT FROM AUTHOR]

Glioblastoma is a highly aggressive tumour of the central nervous system, characterised by poor prognosis irrespective of the applied treatment. The aim of our study was to analyse whether the molecular markers of glioblastoma (i.e. TP53 and IDH1 mutations, CDKN2A deletion, EGFR amplification, chromosome 7 polysomy and EGFRvIII expression) could be associated with distinct prognosis and/or response to the therapy. Moreover, we describe a method which allows for a reliable, as well as time- and cost-effective, screening for EGFR amplification and chromosome 7 polysomy with quantitative Real-Time PCR at DNA level. In the clinical data, only the patient’s age had prognostic significance (continuous: HR = 1.04; p<0.01). At the molecular level, EGFRvIII expression was associated with a better prognosis (HR = 0.37; p = 0.04). Intriguingly, EGFR amplification was associated with a worse outcome in younger patients (HR = 3.75; p<0.01) and in patients treated with radiotherapy (HR = 2.71; p = 0.03). We did not observe any difference between the patients with the amplification treated with radiotherapy and the patients without such a treatment. Next, EGFR amplification was related to a better prognosis in combination with the homozygous CDKN2A deletion (HR = 0.12; p = 0.01), but to a poorer prognosis in combination with chromosome 7 polysomy (HR = 14.88; p = 0.01). Importantly, the results emphasise the necessity to distinguish both mechanisms of the increased EGFR gene copy number (amplification and polysomy). To conclude, although the data presented here require validation in different groups of patients, they strongly advocate the consideration of the patient’s tumour molecular characteristics in the selection of the therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The number of endometrial cancer (EC) cases is constantly growing. However, the current diagnostic approach is still rather imprecise, leaving 1/3 of patients temporarily undiagnosed. Moreover, final diagnosis is made after the surgery. That mean the histology of tumor, which influences scope of resection, is uncertain during procedure. This results in over- and undertreatment of EC patients. Those diagnostic problems might be solved by liquid biopsy—a new, minimally invasive method to obtain tumor biomarkers. Therefore, this study aimed to evaluate the usefulness of information obtained from liquid biopsy components (tumor educated platelets and circulating tumor DNA) coupled with random forest algorithm and deep neural networks to diagnose EC patients and evaluate tumor histology preoperatively. Background: Liquid biopsy is a minimally invasive collection of a patient body fluid sample. In oncology, they offer several advantages compared to traditional tissue biopsies. However, the potential of this method in endometrial cancer (EC) remains poorly explored. We studied the utility of tumor educated platelets (TEPs) and circulating tumor DNA (ctDNA) for preoperative EC diagnosis, including histology determination. Methods: TEPs from 295 subjects (53 EC patients, 38 patients with benign gynecologic conditions, and 204 healthy women) were RNA-sequenced. DNA sequencing data were obtained for 519 primary tumor tissues and 16 plasma samples. Artificial intelligence was applied to sample classification. Results: Platelet-dedicated classifier yielded AUC of 97.5% in the test set when discriminating between healthy subjects and cancer patients. However, the discrimination between endometrial cancer and benign gynecologic conditions was more challenging, with AUC of 84.1%. ctDNA-dedicated classifier discriminated primary tumor tissue samples with AUC of 96% and ctDNA blood samples with AUC of 69.8%. Conclusions: Liquid biopsies show potential in EC diagnosis. Both TEPs and ctDNA profiles coupled with artificial intelligence constitute a source of useful information. Further work involving more cases is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Testicular germ cell tumors (GCTs) are the most common malignancies in young males. The current treatment regimens are usually highly effective and curative. Nevertheless, a portion of patients presents with recurrence or succumbs due to the disease. There is an undoubtful necessity to investigate new prognostic markers to stratify the risk of such events. The current study aimed to evaluate the prognostic significance of markers of the tumor microenvironment and systemic inflammation markers in GCTs. We found that low expression of immune checkpoint proteins VISTA (V-domain Ig suppressor of T cell activation) and PD-L1 (programmed death-ligand 1) on tumor-associated immune cells and elevated inflammatory marker platelet-to-lymphocyte ratio are associated with a higher risk of events in testicular GCTs. It indicates a role of both local anti-tumor immune response and systemic inflammation in these tumors. In the current study, we aimed to investigate whether expression of immune checkpoint proteins (V-domain Ig suppressor of T cell activation (VISTA) and programmed death-ligand 1 (PD-L1)) and markers of systemic inflammation could predict progression/relapse and death in the cohort of 180 patients with testicular germ-cell tumors (GCTs). Expression of PD-L1 and VISTA was assessed by immunohistochemistry utilizing tissue microarrays. To estimate systemic inflammation neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) were calculated. We found high PD-L1 and VISTA expression on tumor-associated immune cells (TAICs) in 89 (49.44%) and 63 (37.22%) of GCTs, respectively, whereas tumor cells besides trophoblastic elements were almost uniformly negative. High PD-L1 was associated with seminomatous histology and lower stage. Relapses in stage I patients occurred predominantly in cases with low numbers of PD-L1 and VISTA-expressing TAICs. In stage II/III disease, the combination of low VISTA-expressing TAICs and high PLR was identified as predictor of shorter event-free survival (HR 4.10; 1.48–11.36, p = 0.006) and overall survival (HR 15.56, 95% CI 1.78–135.51, p = 0.001) independently of tumor histology and location of metastases. We demonstrated that the assessment of immune checkpoint proteins on TAICs may serve as a valuable prognostic factor in patients with high-risk testicular GCTs. Further study is warranted to explore the predictive utility of these biomarkers in GCTs. [ABSTRACT FROM AUTHOR]