SUMMARY Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localised therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors that showed differential risk of recurrence. The higher risk subtype was characterised by loss of 9q including TSC1, increased KI67 labelling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone-lysine demethylase KDM6A were present in non-invasive tumors from females than males.

Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/− mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/− mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical – basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analysis of tumour genomes from mice chronically exposed to one of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-Trichloropropane (TCP), a haloalkane and pollutant of drinking water, and find these and other signatures in human tumour genomes. We define the cross-species genomic landscape of tumours induced by an important compendium of agents with relevance to human health.

Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.

Magnetic resonance imaging was used to study the effect of weight loss on three fat depots: the visceral and subcutaneous abdominal depots and the subcutaneous depot at trochanter level. Changes in fat depots were compared with changes in circumference measures and the waist-hip ratio (WHR) in obese men (n = 38) and women (n = 40). Mean weight loss was (mean +/- SD) 12.9 +/- 3.5 kg (P < 0.001). The proportional reduction of fat was largest in the visceral depot (men 40%, women 33%). Less fat was lost subcutaneously, especially at trochanter level (men 29%, women 26%). WHR decreased significantly in both sexes (P < 0.001). Change in WHR was not significantly related to the absolute reduction in visceral fat. Total body-fat loss showed a stronger association with subcutaneous fat loss than with visceral fat loss. The findings suggest that fat distribution may change with weight loss, particularly by the loss of visceral fat, but changes in WHR are not appropriate for evaluating changes in this fat depot.

Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.

Oral squamous cell carcinoma (OSCC) is a prevalent cancer with poor prognosis. Most OSCC progresses via a non-malignant stage called dysplasia. Effective treatment of dysplasia prior to potential malignant transformation is an unmet clinical need. To identify markers of early disease, we performed RNA sequencing of 19 matched HPV negative patient trios: normal oral mucosa, dysplasia and associated OSCC. We performed differential gene expression, principal component and correlated gene network analysis using these data. We found differences in the immune cell signatures present at different disease stages and were able to distinguish early events in pathogenesis, such as upregulation of many HOX genes, from later events, such as down-regulation of adherens junctions. We herein highlight novel coding and non-coding candidates for involvement in oral dysplasia development and malignant transformation, and speculate on how our findings may guide further translational research into the treatment of oral dysplasia.

The effect of weight reduction on serum lipids in relation to visceral fat accumulation was studied in 78 healthy obese subjects (40 premenopausal women and 38 men) aged 27-51 years and with an initial body mass index of 30.7±2.2 kg/m 2 (mean±SD). The subjects received a 4.2 MJ/day energy-deficit diet for 13 weeks. Magnetic resonance imaging was used to assess abdominal fat areas before and after weight loss. Weight reductions of 12.6±3.2 kg in men and 11.7±3.8 kg in women resulted in larger reductions in the fasting serum levels of total cholesterol (p<0.05), low density lipoprotein cholesterol (p=0.06), and triglycerides (p<0.01) and a larger increase in the high density lipoprotein cholesterol/low density lipoprotein cholesterol ratio (p=0.05) in men compared with women. Men also lost more visceral fat (p<0.0001), whereas the reductions in the total and subcutaneous abdominal fat depots were similar. In women, viscera) fat loss was significantly related with an increase of the high density lipoprotein cholesterol level, independent of the degree of total fat loss. In men, however, no significant correlations were observed between changes in visceral fat and any of the serum lipids. Comparisons of average changes in obese men and women suggest that visceral fat loss is associated with an improvement of the serum lipid profile. However, correlation analysis does not support a critical role of visceral fat in determining serum lipid concentrations on an individual level, except for an improvement of the high density lipoprotein cholesterol level with visceral fat loss in obese women. rence of several metabolic aberrations of obesity, such as diabetes mellitus and coronary heart disease, are related to body fat distribution.12 A relative predominance of visceral fat in the abdominal region seems to be a more important predictor for these metabolic disorders than is total body fatness.In numerous studies, the influence of weight reduction on changes in serum lipids in obesity has been examined. There have been only a few studies investigating the relations between changes in body fat distribution and changes in serum lipid levels in response to weight reduction.