Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: An eco-epidemiological community-based cohort study in Brazil.

Background: Zoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira, the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems. Methods: We conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of 'rattiness', our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk. Results: The estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95% CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95% CI 1.05, 1.53). Conclusions: These findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention. Funding: This work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB/JCB0020/2016). MTE was supported by a Medical Research UK doctorate studentship. FBS participated in this study under a FAPESB doctorate scholarship.

Pediatric burden and seasonality of human metapneumovirus over 5 years in Managua, Nicaragua.

BACKGROUND: Human metapneumovirus (hMPV) is an important cause of pediatric respiratory infection. We leveraged the Nicaraguan Pediatric Influenza Cohort Study (NPICS) to assess the burden and seasonality of symptomatic hMPV infection in children. METHODS: NPICS is an ongoing prospective study of children in Managua, Nicaragua. We assessed children for hMPV infection via real-time reverse-transcription polymerase chain reaction (RT-PCR). We used classical additive decomposition analysis to assess the temporal trends, and generalized growth models (GGMs) were used to estimate effective reproduction numbers. RESULTS: From 2011 to 2016, there were 564 hMPV symptomatic infections, yielding an incidence rate of 5.74 cases per 100 person-years (95% CI 5.3, 6.2). Children experienced 3509 acute lower respiratory infections (ALRIs), of which 160 (4.6%) were associated with hMPV infection. Children under the age of one had 55% of all symptomatic hMPV infections (62/112) develop into hMPV-associated ALRIs and were five times as likely as children over one to have an hMPV-associated ALRI (rate ratio 5.5 95% CI 4.1, 7.4 p < 0.001). Additionally, symptomatic reinfection with hMPV was common. In total, 87 (15%) of all observed symptomatic infections were detected reinfections. The seasonality of symptomatic hMPV outbreaks varied considerably. From 2011 to 2016, four epidemic periods were observed, following a biennial seasonal pattern. The mean ascending phase of the epidemic periods were 7.7 weeks, with an overall mean estimated reproductive number of 1.2 (95% CI 1.1, 1.4). CONCLUSIONS: Symptomatic hMPV infection was associated with substantial burden among children in the first year of life. Timing and frequency of symptomatic hMPV incidence followed biennial patterns.

Population dynamics of synanthropic rodents after a chemical and infrastructural intervention in an urban low-income community.

Synanthropic rodents are ubiquitous in low-income communities and pose risks for human health, as they are generally resistant to control programs. However, few or no studies have evaluated the long-term effect of chemical and infrastructural interventions on rodent population dynamics, especially in urban low-income communities, or evaluated the potential recovery of their population following interventions. We conducted a longitudinal study in a low-income community in the city of Salvador (BA, Brazil) to characterize the effect of interventions (chemical and infrastructural) on the dynamics of rodent population, and documented the post-intervention recovery of their population. We evaluated the degree of rodent infestation in 117 households/sampling points over three years (2014-2017), using tracking plates, a proxy for rodent abundance/activity. We reported a significant lower rodent activity/abundance after the chemical and infrastructural interventions (Z = -4.691 (p < 0.001)), with track plate positivity decreasing to 28% from 70% after and before interventions respectively. Therefore, the combination of chemical and infrastructural interventions significantly decreased the degree of rodent infestation in the study area. In addition, no rodent population rebound was recorded until almost a year post-intervention, and the post-intervention infestation level did not attain the pre-intervention level all through the study. Moreover, among pre-treatment conditions, access to sewer rather than the availability of food was the variable most closely associated with household rodent infestation. Our study indicates that Integrated Pest Management (IPM)-approaches are more effective in reducing rodent infestation than the use of a single method. Our findings will be useful in providing guidance for long-term rodent control programs, especially in urban low-income communities.

Spatiotemporal trends in bed bug metrics: New York City.

Bed bug outbreaks pose a major challenge in urban environments and cause significant strain on public resources. Few studies have systematically analyzed this insect epidemic or the potential effects of policies to combat bed bugs. Here we use three sources of administrative data to characterize the spatial-temporal trends of bed bug inquiries, complaints, and reports in New York City. Bed bug complaints have significantly decreased (p < 0.01) from 2014-2020, the absolute number of complaints per month dropping by half (875 average complaints per month to 440 average complaints per month); conversely, complaints for other insects including cockroaches and flies did not decrease over the same period. Despite the decrease of bed bug complaints, areas with reported high bed bug infestation tend to remain infested, highlighting the persistence of these pests. There are limitations to the datasets; still the evidence available suggests that interventions employed by New York City residents and lawmakers are stemming the bed bug epidemic and may serve as a model for other large cities.

Factors Impacting Postoperative Opioid Use Among Patients Undergoing Implantation of Inflatable Penile Prosthesis.

BACKGROUND: While there is an increasing burden of chronic postoperative opioid use and opioid abuse in the United States, opioid use following inflatable penile prosthesis (IPP) surgery has not been well described. AIM: Describe postoperative opioid use following IPP surgery. METHODS: Seventy-four consecutive patients undergoing IPP implantation by a single surgeon were enrolled. Self-reported diaries tracked the type and amount of medication taken for 2 weeks following IPP surgery. High opioid consumers were defined as those consuming more than the median amount (10 mg) of opioids during the first 2 weeks postoperatively. Multivariate analyses were performed using stepwise backward elimination. OUTCOMES: Quantification of opioid use postoperatively and factors related to high opioid use. RESULTS: Fifty-six patients were included after 7 were excluded for preoperative opioid use and 11 were excluded for inability to contact. Median age was 67.5. Devices used were Boston Scientific (41, 73%) and Coloplast (15, 27%). All patients received local anesthetic. Most surgeries (44, 79%) were performed as outpatient. Preoperative analgesia with acetaminophen, celecoxib, and pregabalin was administered in 44 (78%), 44 (78%), and 28 (50%) of cases respectively; 32 (57%) of patients received 2 medications, 21 (36%) received three medications. In hospital median morphine equivalents was 7.5 (interquartile range [IQR] 0-7.5). Oxycodone prescribed at discharge was 50 mg (29, 52%), 75 mg (4; 7%), and 100 mg (23; 41%). Median milligrams of oxycodone used was 10 mg (IQR 0-23.5) at 7 days and 10 (IQR 0-37.5) at 14 days postdischarge. On univariate analysis, factors associated with an increased likelihood of high opioid use were morphine equivalents utilized in hospital (odds ratio [OR] 1.13, P < .05) and milligrams oxycodone prescribed at discharge (OR 1.05, P < .001) while patient demographics, procedure characteristics, and analgesic types were not found to be predictive of high opioid use. On multivariate analysis, milligrams oxycodone prescribed at discharge (OR 1.04, P < .005) were associated with an increased likelihood of high opioid use after discharge. CLINICAL IMPLICATIONS: Increased understanding of opioid use after IPP surgery may improve prescribing patterns after discharge. STRENGTHS & LIMITATIONS: This study quantified post discharge opioid use over the first 14 postoperative days. It is limited by single surgeon, small sample size, and retrospective design. CONCLUSION: Provider opioid prescribing patterns were associated with high opioid consumption postoperatively and a substantial amount of opioids prescribed at discharge remain unused by patients, suggesting that we can reduce or replace the amount of opioids that are prescribed. Ehlers ME, Mohan CS, Akerman JP, et al. Factors Impacting Postoperative Opioid Use Among Patients Undergoing Implantation of Inflatable Penile Prosthesis. J Sex Med 2021;18:1915-1920.

A multivariate geostatistical framework for combining multiple indices of abundance for disease vectors and reservoirs: a case study of rattiness in a low-income urban Brazilian community.

A key requirement in studies of endemic vector-borne or zoonotic disease is an estimate of the spatial variation in vector or reservoir host abundance. For many vector species, multiple indices of abundance are available, but current approaches to choosing between or combining these indices do not fully exploit the potential inferential benefits that might accrue from modelling their joint spatial distribution. Here, we develop a class of multivariate generalized linear geostatistical models for multiple indices of abundance. We illustrate this novel methodology with a case study on Norway rats in a low-income urban Brazilian community, where rat abundance is a likely risk factor for human leptospirosis. We combine three indices of rat abundance to draw predictive inferences on a spatially continuous latent process, rattiness, that acts as a proxy for abundance. We show how to explore the association between rattiness and spatially varying environmental factors, evaluate the relative importance of each of the three contributing indices and assess the presence of residual, unexplained spatial variation, and identify rattiness hotspots. The proposed methodology is applicable more generally as a tool for understanding the role of vector or reservoir host abundance in predicting spatial variation in the risk of human disease.

Influence of Rainfall on Leptospira Infection and Disease in a Tropical Urban Setting, Brazil.

The incidence of hospitalized leptospirosis patients was positively associated with increased precipitation in Salvador, Brazil. However, Leptospira infection risk among a cohort of city residents was inversely associated with rainfall. These findings indicate that, although heavy rainfall may increase severe illness, Leptospira exposures can occur year-round.

Leptospira yasudae sp. nov. and Leptospira stimsonii sp. nov., two new species of the pathogenic group isolated from environmental sources.

Four spirochetes (F1T, B21, YaleT and AMB6-RJ) were isolated from environmental sources: F1T and B21 from soils of an urban slum community in Salvador (Brazil), YaleT from river water in New Haven, Connecticut (USA) and AMB6-RJ from a pond in a horse farm in Rio de Janeiro (Brazil). Isolates were helix-shaped, aerobic, highly motile and non-virulent in a hamster model of infection. Draft genomes of the strains were obtained and analysed to determine the relatedness to other species of the genus Leptospira. The analysis of 498 core genes showed that strains F1T/B21 and YaleT/AMB6-RJ formed two distinct phylogenetic clades within the 'Pathogens' group (group I). The average nucleotide identity (ANI) values of strains F1T/B21 and YaleT/AMB6-RJ to other previously described Leptospira species were below <84 % and <82 %, respectively, which confirmed that these isolates should be classified as representatives of two novel species. Therefore, we propose Leptospirayasudae sp. nov. and Leptospirastimsonii sp. nov. as new species in the genus Leptospira. The type strains are F1T (=ATCC-TSD-163=KIT0259=CLEP00287) and YaleT (=ATCC-TDS-162=KIT0258=CLEP00288), respectively.

A Case Study of Cimex lectularius L. (Hemiptera: Cimicidae) Infestations in an Office Environment.

Most field studies on Cimex lectularius are conducted in residential or hospitality industrial settings. Cimex lectularius infestations in office settings are reported, but are rarely studied. An office environment (~875 m2) consisting of 105 cubicles or pod-seating areas with persistent C. lectularius sightings over a 2-yr period was evaluated for 90 d through intensive trapping to determine C. lectularius distribution and to eliminate the infestation. The study area was partially occupied during the study period. Two treatments of amorphous silica dust (112.5 g dust in total) were applied 29 and 57 d after the first day of monitoring. A total of 32 C. lectularius were captured by interceptors over a period of 55 d. Dry ice traps captured eight additional C. lectularius. Visual inspections identified one chair with live C. lectularius and eggs. The infestation was eliminated on 69 d after initial installation of interceptors. Spatial analysis using Ripley's K and L functions showed a high level of aggregation up to a 15 meter scale. Dispersal of C. lectularius in office settings was limited. Intensive trapping plus limited insecticide dust treatments effectively detected and eliminated C. lectularius.

Engaging Stakeholders and Patient Partners.

Recent advances in engagement of stakeholders and patient partners in clinical research have bridged the disconnect between researchers and stakeholders, resulting in improved research goals with relevant outcomes, increased clinical trial enrollment, and improved communication of research results. This article focuses on the mechanisms, challenges, and benefits of patient and stakeholder engagement, with strategies for improvement. The 3 stages of clinical research and key iterative steps to create a reciprocal relationship are presented. Despite recent advances in stakeholder engagement, additional investigation and improved reporting of methods will facilitate strong reciprocal relationships between researchers and stakeholders.

Quantification of pathogenic Leptospira in the soils of a Brazilian urban slum.

BACKGROUND: Leptospirosis is an important zoonotic disease that causes considerable morbidity and mortality globally, primarily in residents of urban slums. While contact with contaminated water plays a critical role in the transmission of leptospirosis, little is known about the distribution and abundance of pathogenic Leptospira spp. in soil and the potential contribution of this source to human infection. METHODS/PRINCIPAL FINDINGS: We collected soil samples (n = 70) from three sites within an urban slum community endemic for leptospirosis in Salvador, Brazil. Using qPCR of Leptospira genes lipl32 and 16S rRNA, we quantified the pathogenic Leptospira load in each soil sample. lipl32 qPCR detected pathogenic Leptospira in 22 (31%) of 70 samples, though the median concentration among positive samples was low (median = 6 GEq/g; range: 4-4.31×102 GEq/g). We also observed heterogeneity in the distribution of pathogenic Leptospira at the fine spatial scale. However, when using 16S rRNA qPCR, we detected a higher proportion of Leptospira-positive samples (86%) and higher bacterial concentrations (median: 4.16×102 GEq/g; range: 4-2.58×104 GEq/g). Sequencing of the qPCR amplicons and qPCR analysis with all type Leptospira species revealed that the 16S rRNA qPCR detected not only pathogenic Leptospira but also intermediate species, although both methods excluded saprophytic Leptospira. No significant associations were identified between the presence of pathogenic Leptospira DNA and environmental characteristics (vegetation, rat activity, distance to an open sewer or a house, or soil clay content), though samples with higher soil moisture content showed higher prevalences. CONCLUSION/SIGNIFICANCE: This is the first study to successfully quantify the burden of pathogenic Leptospira in soil from an endemic region. Our results support the hypothesis that soil may be an under-recognized environmental reservoir contributing to transmission of pathogenic Leptospira in urban slums. Consequently, the role of soil should be considered when planning interventions aimed to reduce the burden of leptospirosis in these communities.

Correction: Cathelicidin Insufficiency in Patients with Fatal Leptospirosis.

[This corrects the article DOI: 10.1371/journal.ppat.1005943.].

Detection of Upper Tract Urothelial Malignancies by Computed Tomography Urography in Patients Referred for Hematuria at a Large Tertiary Referral Center.

OBJECTIVE: To evaluate the age-stratified prevalence of upper tract urothelial malignancies diagnosed on computed tomography urography in a large cohort of patients referred for initial evaluation of hematuria. MATERIALS AND METHODS: A total of 1123 consecutive adults without a history of urothelial cancer underwent initial computed tomography urography for gross hematuria (n = 652), microscopic hematuria (n = 457), or unspecified hematuria (n = 14) at a single institution from October 2006 to October 2012. Imaging findings suggestive of urothelial lesions were correlated with clinical information, including cystoscopy, cytology, and surgical pathology reports. Patients subsequently diagnosed with urothelial cancer following a normal radiographic evaluation were identified and analyzed. Age, gender, smoking history, and location and type of malignancy were analyzed. RESULTS: Upper tract urothelial cancer was detected in 4 (0.36%) patients, with a mean age of 66.5 years. All 4 patients presented with gross hematuria and were current or former smokers. None of the 535 patients under age 55 who underwent computed tomography urography were diagnosed with upper tract disease regardless of age, smoking history, or degree of hematuria. Likewise, no upper tract cancers were detected in patients referred for microscopic hematuria, regardless of age. CONCLUSION: Detection of upper tract urothelial cancer by computed tomography urography is exceedingly rare in patients presenting at a tertiary referral center with hematuria, particularly in the lower risk strata (younger age, microscopic hematuria). Further investigation into risk-stratified approaches to imaging for hematuria workup is warranted to minimize unnecessary costs and radiation exposure.

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis.

Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation.

The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer.

Dual Chromatin and Cytoskeletal Remodeling by SETD2.

Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy. These data now identify SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton and show a requirement for methylation in maintenance of genomic stability and the integrity of both the tubulin and histone codes.

A Comparative Assessment of Track Plates to Quantify Fine Scale Variations in the Relative Abundance of Norway Rats in Urban Slums.

Norway rats (Rattus norvegicus) living in urban environments are a critical public health and economic problem, particularly in urban slums where residents are at a higher risk for rat borne diseases, yet convenient methods to quantitatively assess population sizes are lacking. We evaluated track plates as a method to determine rat distribution and relative abundance in a complex urban slum environment by correlating the presence and intensity of rat-specific marks on track plates with findings from rat infestation surveys and trapping of rats to population exhaustion. To integrate the zero-inflated track plate data we developed a two-component mixture model with one binary and one censored continuous component. Track plate mark-intensity was highly correlated with signs of rodent infestation (all coefficients between 0.61 and 0.79 and all p-values < 0.05). Moreover, the mean level of pre-trapping rat-mark intensity on plates was significantly associated with the number of rats captured subsequently (Odds ratio1.38; 95% CI 1.19-1.61) and declined significantly following trapping (Odds ratio 0.86; 95% CI 0.78-0.95). Track plates provided robust proxy measurements of rat abundance and distribution and detected rat presence even when populations appeared 'trapped out'. Tracking plates are relatively easy and inexpensive methods that can be used to intensively sample settings such as urban slums, where traditional trapping or mark-recapture studies are impossible to implement, and therefore the results can inform and assess the impact of targeted urban rodent control campaigns.

Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.

BACKGROUND: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model. METHODS: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes. RESULTS: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered. CONCLUSION: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.

The somatic genomic landscape of chromophobe renal cell carcinoma.

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.

Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects.

Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins. For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1. How these mutations alter the chromatin landscape and transcriptional program in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcript profiles associated with mutations in chromatin regulators in a large cohort of primary human kidney tumors. By associating variation in chromatin organization with mutations in SETD2, which encodes the enzyme responsible for H3K36 trimethylation, we found that changes in chromatin accessibility occurred primarily within actively transcribed genes. This increase in chromatin accessibility was linked with widespread alterations in RNA processing, including intron retention and aberrant splicing, affecting ∼25% of all expressed genes. Furthermore, decreased nucleosome occupancy proximal to misspliced exons was observed in tumors lacking H3K36me3. These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer. Detecting the functional consequences of specific mutations in chromatin regulatory proteins in primary human samples could ultimately inform the therapeutic application of an emerging class of chromatin-targeted compounds.