Microbial constituents in the gastrointestinal tract, the urine and prostate tissue are being linked with clinical differences in prostate cancer, and a recent meta-analysis has linked periodontal disease to this cancer. Several hypotheses exist regarding how specific bacteria can contribute towards the development of prostate cancer. Recovering microbial genomes, and their genomic features, from clinical samples and investigating fine-scale taxonomy is a critical first step in investigating...
Androgen receptor (AR) activation alters chromatin structure in prostate cancer (PC) cells, but its impact in nonmalignant prostate epithelial cells (NPEC) remains poorly characterized due to lack of representative models. We leveraged our previously established NPEC (RWPE-1-AR and RWPE-1-Ctrl) and PC (LNCaP-pcDNA3.1 and LNCaP-ARhi) cell models to profile androgen-driven chromatin responses using assay for transposase-accessible chromatin with sequencing (ATAC-seq). In the absence of androgen,...
Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology¹. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the...
The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes...
Although chemotherapy in colorectal cancer (CRC) primarily targets epithelial tumor cells, the epithelial cell-intrinsic mechanisms underlying heterogeneous treatment responses remain poorly understood. We integrated the genomic, transcriptomic, and in vitro drug response profiles of CRC patient-derived tumor organoids (PDTOs) with functional assays to identify epithelial cell-intrinsic determinants of chemotherapy response. An epithelial interferon-stimulated gene (ISG) program, reflecting...
CONCLUSIONS: This prospective cohort study does not support the hypothesis that higher maternal intake of vitamins A, C, D, and E during pregnancy would decrease risk of type 1 diabetes in the child. Corroborated with previous evidence, our findings support a general pattern of null associations.
INTRODUCTION: Fighter pilots are exposed to high +Gz forces, helmet-mounted equipment, and extreme head positions that potentially cause cervical spine degeneration and pain. This study aimed to investigate whether individual +Gz exposure, quantified by Fatigue Index (FI), predicts cervical spine degenerative changes and neck pain over a 10-yr follow-up.
CONCLUSIONS AND CLINICAL IMPLICATIONS: PI-RADS score 5 is associated with elevated risk of adverse outcomes. The presented clinically strong endpoints have potential to affect decision-making in MRI-based PCa diagnosis and prognosis.
Cell nuclei are often used to assess cell health, but how their shapes vary in normal tissues and how they respond to mechanical forces is not well understood. Here, we describe deep invaginations of the nuclear envelope (DINEs) as common features of epithelial cell nuclei. After their formation, DINEs exist independently of the cytoskeleton, depend on A-type lamins, and emerge in response to cell crowding, contact inhibition, and tissue maturation. High-resolution imaging shows that, in...
Fibroblast growth factor receptor (FGFR) alterations are targetable in metastatic urothelial carcinoma (mUC). Identifying FGFR alterations currently requires tissue testing, which is limited by sample availability and cancer heterogeneity. Plasma circulating tumor DNA (ctDNA) offers a complementary testing strategy, but the added value of ctDNA relative to conventional FGFR alteration assessment remains unclear. Here, in a prospective, multicentre study, we show that ctDNA testing has high...
Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) are slow- or non-progressing epileptogenic tumors, typically occurring in young adults. These tumors are highly calcified and exhibit both diffuse growth and oligodendroglioma-like patterns. Epithelioid glioblastomas (E-GB) are rare and aggressive variants of isocitrate dehydrogenase wildtype glioblastomas (GB), associated with poor overall survival. Both PLNTY and E-GB often carry oncogenic BRAF V600E mutation (BRAF(V600E)). In...
Lynch syndrome is characterized by the development of microsatellite-instable cancers that share neoantigens, offering an opportunity for targeted immunotherapy. NOUS-209 is a heterologous prime-boost cancer vaccine in clinical development, employing viral vectors encoding 209 shared neoantigen peptides derived from frameshift mutations (FSM) commonly found in microsatellite-instable tumors. In this study, we investigated the presence and dynamics of NOUS-209 targeted FSMs in both primary and...
CONCLUSIONS: This study provides the most comprehensive resource to date characterizing somatic alterations at the AR locus. Our clinicogenomic analysis establishes the repertoire and clinical relevance of AR genotypes in mCRPC, informing efforts to target renewed AR dependency.
