RESUMEN
p53 and p19(ARF) are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19(ARF) deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19(ARF)-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Redes Reguladoras de Genes , Genes Supresores de Tumor , Neoplasias/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular Tumoral , Clonación Molecular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Genes p53 , Genómica/métodos , Humanos , Ratones , Ratones Noqueados , Mutagénesis Insercional , Neoplasias/metabolismo , Análisis de Secuencia de ADNRESUMEN
Retroviral insertional mutagenesis is a powerful tool for identifying putative cancer genes in mice. To uncover the regulatory mechanisms by which common insertion loci affect downstream processes, we supplemented genotyping data with genome-wide mRNA expression profiling data for 97 tumors induced by retroviral insertional mutagenesis. We developed locus expression signature analysis, an algorithm to construct and interpret the differential gene expression signature associated with each common insertion locus. Comparing locus expression signatures to promoter affinity profiles allowed us to build a detailed map of transcription factors whose protein-level regulatory activity is modulated by a particular locus. We also predicted a large set of drugs that might mitigate the effect of the insertion on tumorigenesis. Taken together, our results demonstrate the potential of a locus-specific signature approach for identifying mammalian regulatory mechanisms in a cancer context.
Asunto(s)
Carcinogénesis/metabolismo , Biología Computacional/métodos , Daño del ADN , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Variación Genética , Neoplasias/genética , Análisis de Varianza , Animales , Carcinogénesis/genética , Análisis por Conglomerados , Inhibidores Enzimáticos/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Ensayos Analíticos de Alto Rendimiento/métodos , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3RESUMEN
Retroviral and transposon-based insertional mutagenesis (IM) screens are widely used for cancer gene discovery in mice. Exploiting the full potential of IM screens requires methods for high-throughput sequencing and mapping of transposon and retroviral insertion sites. Current protocols are based on ligation-mediated PCR amplification of junction fragments from restriction endonuclease-digested genomic DNA, resulting in amplification biases due to uneven genomic distribution of restriction enzyme recognition sites. Consequently, sequence coverage cannot be used to assess the clonality of individual insertions. We have developed a novel method, called shear-splink, for the semiquantitative high-throughput analysis of insertional mutations. Shear-splink employs random fragmentation of genomic DNA, which reduces unwanted amplification biases. Additionally, shear-splink enables us to assess clonality of individual insertions by determining the number of unique ligation points (LPs) between the adapter and genomic DNA. This parameter serves as a semiquantitative measure of the relative clonality of individual insertions within heterogeneous tumors. Mixing experiments with clonal cell lines derived from mouse mammary tumor virus (MMTV)-induced tumors showed that shear-splink enables the semiquantitative assessment of the clonality of MMTV insertions. Further, shear-splink analysis of 16 MMTV- and 127 Sleeping Beauty (SB)-induced tumors showed enrichment for cancer-relevant insertions by exclusion of irrelevant background insertions marked by single LPs, thereby facilitating the discovery of candidate cancer genes. To fully exploit the use of the shear-splink method, we set up the Insertional Mutagenesis Database (iMDB), offering a publicly available web-based application to analyze both retroviral- and transposon-based insertional mutagenesis data.
Asunto(s)
ADN de Neoplasias/genética , Bases de Datos Genéticas , Virus del Tumor Mamario del Ratón , Mutagénesis Insercional , Infecciones por Retroviridae/genética , Infecciones Tumorales por Virus/genética , Animales , Análisis Mutacional de ADN/métodos , RatonesRESUMEN
Background: Interferon (IFN) responses are critical in the resolution of viral infections and are actively targeted by many viruses. They also play a role in inducing protective responses after vaccination and have been successfully tested as vaccine adjuvants. IFN responses are well conserved and function very similar in teleosts and mammals. Like in mammals, IFN responses in piscine cells are initiated by intracellular detection of the viral infection by different pattern recognition receptors. Upon the recognition of viral components, IFN responses are rapidly induced to combat the infection. However, many viruses may still replicate and be able to inhibit or circumvent the IFN response by different means. Methods: By employing CRISPR Cas9 technology, we have disrupted proteins that are central for IFN signaling in the salmonid cell line CHSE-214. We successfully generated KO clones for the mitochondrial antiviral signaling protein MAVS, the transcription factors IRF3 and IRF7-1, as well as a double KO for IRF7-1/3 using an optimized protocol for delivery of CRISPR-Cas ribonucleoproteins through nucleofection. Results: We found that MAVS and IRF3 KOs inhibited IFN and IFN-stimulated gene induction after intracellular poly I:C stimulation as determined through gene expression and promoter activation assays. In contrast, the IRF7-1 KO had no clear effect. This shows that MAVS and IRF3 are essential for initiation of intracellular RNA-induced IFN responses in CHSE-214 cells. To elucidate viral interference with IFN induction pathways, the KOs were infected with Salmon alphavirus 3 (SAV3) and infectious pancreatic necrosis virus (IPNV). SAV3 infection in control and IRF7-1 KO cells yielded similar titers and no cytopathic effect, while IRF3 and MAVS KOs presented with severe cytopathic effect and increased titers 6 days after SAV 3 infection. In contrast, IPNV yields were reduced in IRF3 and MAVS KOs, suggesting a dependency on interactions between viral proteins and pattern recognition receptor signaling components during viral replication. Conclusion: Aside from more insight in this signaling in salmonids, our results indicate a possible method to increase viral titers in salmonid cells.
Asunto(s)
Virus de la Necrosis Pancreática Infecciosa , Salmonidae , Animales , Salmonidae/genética , Sistemas CRISPR-Cas , Transducción de Señal , Línea Celular , Salmón/genética , MamíferosRESUMEN
The intraperitoneal route is favored for administration of inactivated and attenuated vaccines in Atlantic salmon. Nevertheless, the immune responses in the teleost peritoneal cavity (PerC) are still incompletely defined. In this study, we investigated the B cell responses after intraperitoneal Piscirickettsia salmonis (P. salmonis) challenge of Atlantic salmon, focusing on the local PerC response versus responses in the lymphatic organs: spleen and head kidney. We observed a major increase of leukocytes, total IgM antibody secreting cells (ASC), and P. salmonis-specific ASC in the PerC at 3- and 6-weeks post infection (wpi). The increase in ASC frequency was more prominent in the spleen and PerC compared to the head kidney during the observed 6 wpi. The serum antibody response included P. salmonis-specific antibodies and non-specific antibodies recognizing the non-related bacterial pathogen Yersinia ruckeri and the model antigen TNP-KLH. Finally, we present evidence that supports a putative role for the adipose tissue in the PerC immune response.
Asunto(s)
Células Productoras de Anticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Enfermedades de los Peces/inmunología , Cavidad Peritoneal/fisiología , Piscirickettsia/fisiología , Infecciones por Piscirickettsiaceae/inmunología , Salmo salar/inmunología , Tejido Adiposo/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Reacciones Cruzadas , Proteínas de Peces/metabolismo , Inmunidad Humoral , Inmunoglobulina M/metabolismo , Yersinia ruckeri/inmunologíaRESUMEN
MOTIVATION: Cancers are caused by an accumulation of multiple independent mutations that collectively deregulate cellular pathways, e.g. such as those regulating cell division and cell-death. The publicly available Retroviral Tagged Cancer Gene Database (RTCGD) contains the data of many insertional mutagenesis screens, in which the virally induced mutations result in tumor formation in mice. The insertion loci therefore indicate the location of putative cancer genes. Additionally, the presence of multiple independent insertions within one tumor hints towards a cooperation between the insertionally mutated genes. In this study we focus on the detection of statistically significant co-mutations. RESULTS: We propose a two-dimensional Gaussian Kernel Convolution method (2DGKC), a computational technique that identifies the cooperating mutations in insertional mutagenesis data. We define the Common Co-occurrence of Insertions (CCI), signifying the co-mutations that are statistically significant across all different screens in the RTCGD. Significance estimates are made on multiple scales, and the results visualized in a scale space, thereby providing valuable extra information on the putative cooperation. The multidimensional analysis of the insertion data results in the discovery of 86 statistically significant co-mutations, indicating the presence of cooperating oncogenes that play a role in tumor development. Since oncogenes may cooperate with several members of a parallel pathway, we combined the co-occurrence data with gene family information to find significant cooperations between oncogenes and families of genes. We show, for instance, the interchangeable cooperation of Myc insertions with insertions in the Pim family. AVAILABILITY: A list of the resulting CCIs is available at: http://ict.ewi.tudelft.nl/~jeroen/CCI/CCI_list.txt.
Asunto(s)
Familia de Multigenes/genética , Mutagénesis Insercional/métodos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Oncogénicas/metabolismo , Oncogenes/genética , Transducción de Señal , Simulación por Computador , Bases de Datos Genéticas , Modelos Biológicos , Proteínas Oncogénicas/genéticaRESUMEN
Retroviral insertional mutagenesis screens, which identify genes involved in tumor development in mice, have yielded a substantial number of retroviral integration sites, and this number is expected to grow substantially due to the introduction of high-throughput screening techniques. The data of various retroviral insertional mutagenesis screens are compiled in the publicly available Retroviral Tagged Cancer Gene Database (RTCGD). Integrally analyzing these screens for the presence of common insertion sites (CISs, i.e., regions in the genome that have been hit by viral insertions in multiple independent tumors significantly more than expected by chance) requires an approach that corrects for the increased probability of finding false CISs as the amount of available data increases. Moreover, significance estimates of CISs should be established taking into account both the noise, arising from the random nature of the insertion process, as well as the bias, stemming from preferential insertion sites present in the genome and the data retrieval methodology. We introduce a framework, the kernel convolution (KC) framework, to find CISs in a noisy and biased environment using a predefined significance level while controlling the family-wise error (FWE) (the probability of detecting false CISs). Where previous methods use one, two, or three predetermined fixed scales, our method is capable of operating at any biologically relevant scale. This creates the possibility to analyze the CISs in a scale space by varying the width of the CISs, providing new insights in the behavior of CISs across multiple scales. Our method also features the possibility of including models for background bias. Using simulated data, we evaluate the KC framework using three kernel functions, the Gaussian, triangular, and rectangular kernel function. We applied the Gaussian KC to the data from the combined set of screens in the RTCGD and found that 53% of the CISs do not reach the significance threshold in this combined setting. Still, with the FWE under control, application of our method resulted in the discovery of eight novel CISs, which each have a probability less than 5% of being false detections.
Asunto(s)
Mapeo Cromosómico/métodos , Análisis Mutacional de ADN/métodos , Elementos Transponibles de ADN/genética , Genoma Viral/genética , Retroviridae/genética , Análisis de Secuencia de ADN/métodos , Simulación por Computador , Interpretación Estadística de Datos , Pruebas Genéticas/métodos , Modelos Genéticos , Modelos Estadísticos , Alineación de Secuencia/métodosRESUMEN
The nucleotide excision repair (NER) system consists of two sub-pathways, global genome repair (GGR) and transcription-coupled repair (TCR), which exhibit distinct functions in the cellular response to genotoxic stress. Defects in TCR result in prolonged UV light-induced stalling of RNA polymerase II and hypersensitivity to apoptosis induced by UV and certain chemotherapeutic drugs. Here, we show that low doses of UV trigger delayed activation of the stress-induced MAPkinase JNK and its proapoptotic targets c-Jun and ATF-3 in TCR-deficient primary human fibroblasts from Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) patients. This delayed activation of the JNK pathway is not observed in GGR-deficient TCR-proficient XP cells, is independent of functional p53, and is established through repression of the JNK-phosphatase MKP-1 rather than by activation of the JNK kinases MKK4 and 7. Enzymatic reversal of UV-induced cyclobutane pyrimidine dimers (CPDs) by CPD photolyase abrogated JNK activation, MKP-1 repression, and apoptosis in TCR-deficient XPA cells. Ectopic expression of MKP-1 inhibited DNA-damage-induced JNK activity and apoptosis. These results identify both MKP-1 and JNK as sensors and downstream effectors of persistent DNA damage in transcribed genes and suggest a link between the JNK pathway and UV-induced stalling of RNApol II.
Asunto(s)
Apoptosis/efectos de la radiación , Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Transcripción Genética , Línea Celular Transformada , Transformación Celular Viral , Células Cultivadas , Síndrome de Cockayne/genética , Reparación del ADN , Fosfatasa 1 de Especificidad Dual , Fibroblastos/efectos de la radiación , Citometría de Flujo , Humanos , Proteína Fosfatasa 1 , Factor de Transcripción AP-1/metabolismo , Rayos Ultravioleta , Xerodermia Pigmentosa/genética , Proteína de la Xerodermia Pigmentosa del Grupo A/metabolismoRESUMEN
Exposure of human cells to genotoxic agents induces various signaling pathways involved in the execution of stress- and DNA-damage responses. Inappropriate functioning of the DNA-damage response to ionizing radiation (IR) is associated with the human diseases ataxia-telangiectasia (A-T) and Nijmegen Breakage syndrome (NBS). Here, we show that IR efficiently induces Jun/ATF transcription factor activity in normal human diploid fibroblasts, but not in fibroblasts derived from A-T and NBS patients. IR was found to enhance the expression of c-Jun and, in particular, ATF3, but, in contrast to various other stress stimuli, did not induce the expression of c-Fos. Using specific inhibitors, we found that the ATM- and Nibrin1-dependent activation of ATF3 does neither require p53 nor reactive oxygen species, but is dependent on the p38 and JNK MAPkinases. Via these kinases, IR activates ATF-2, one of the transcription factors acting on the atf3 promoter. The activation of ATF-2 by IR resembles ATF-2 activation by certain growth factors, since IR mainly induced the second step of ATF-2 phosphorylation via the stress-inducible MAPkinases, phosphorylation of Thr69. As IR does not enhance ATF-2 phosphorylation in ATM and Nibrin1-deficient cells, both ATF-2 and ATF3 seem to play an important role in the protective response of human cells to IR.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Sistema de Señalización de MAP Quinasas , Radiación Ionizante , Transducción de Señal , Factores de Transcripción/metabolismo , Factor de Transcripción Activador 2 , Factor de Transcripción Activador 3 , Proteínas de la Ataxia Telangiectasia Mutada , Northern Blotting , Western Blotting , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Daño del ADN , Proteínas de Unión al ADN , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Cinética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Nucleares/metabolismo , Estrés Oxidativo , Fosforilación , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Tiempo , Factores de Transcripción/genética , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed the Mouse Mammary Tumor Virus (MMTV) as an insertional mutagen to find both the driver genes and the networks in which they function. Using deep insertion site sequencing we identified around 31000 retroviral integration sites in 604 MMTV-induced mammary tumors from mice with mammary gland-specific deletion of Trp53, Pten heterozygous knockout mice, or wildtype strains. We identified 18 known common integration sites (CISs) and 12 previously unknown CISs marking new candidate cancer genes. Members of the Wnt, Fgf, Fgfr, Rspo and Pdgfr gene families were commonly mutated in a mutually exclusive fashion. The sequence data we generated yielded also information on the clonality of insertions in individual tumors, allowing us to develop a data-driven model of MMTV-induced tumor development. Insertional mutations near Wnt and Fgf genes mark the earliest "initiating" events in MMTV induced tumorigenesis, whereas Fgfr genes are targeted later during tumor progression. Our data shows that insertional mutagenesis can be used to discover the mutational networks, the timing of mutations, and the genes that initiate and drive tumor evolution.
Asunto(s)
Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Virus del Tumor Mamario del Ratón/fisiología , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Neoplasias Mamarias Experimentales/virología , Ratones , Mutagénesis Insercional , Fosfohidrolasa PTEN/genética , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The cyclin dependent kinase (CDK) inhibitors p15, p16, p21, and p27 are frequently deleted, silenced, or downregulated in many malignancies. Inactivation of CDK inhibitors predisposes mice to tumor development, showing that these genes function as tumor suppressors. Here, we describe high-throughput murine leukemia virus insertional mutagenesis screens in mice that are deficient for one or two CDK inhibitors. We retrieved 9,117 retroviral insertions from 476 lymphomas to define hundreds of loci that are mutated more frequently than expected by chance. Many of these loci are skewed toward a specific genetic context of predisposing germline and somatic mutations. We also found associations between these loci with gender, age of tumor onset, and lymphocyte lineage (B or T cell). Comparison of retroviral insertion sites with single nucleotide polymorphisms associated with chronic lymphocytic leukemia revealed a significant overlap between the datasets. Together, our findings highlight the importance of genetic context within large-scale mutation detection studies, and they show a novel use for insertional mutagenesis data in prioritizing disease-associated genes that emerge from genome-wide association studies.
Asunto(s)
Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Mutagénesis Insercional/genética , Neoplasias Experimentales/genética , Animales , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Virus de la Leucemia Murina/genética , Leucemia Linfocítica Crónica de Células B/genética , Linfoma/genética , Masculino , Ratones , Células 3T3 NIH , Polimorfismo de Nucleótido SimpleRESUMEN
Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.
Asunto(s)
Hibridación Genómica Comparativa/métodos , Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , Proteínas Supresoras de Tumor/genética , Animales , Sitios de Unión/genética , Línea Celular Tumoral , Elementos Transponibles de ADN/genética , Femenino , Genómica/métodos , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutagénesis Insercional , Mutación , Proteína Homeótica Nanog , Neoplasias/metabolismo , Neoplasias/patología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Especificidad de la Especie , Células Madre/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Retroviral insertional mutagenesis screens have been used for many years as a tool for cancer gene discovery. In recent years, completion of the mouse genome sequence as well as improved technologies for cloning and sequencing of retroviral insertions have greatly facilitated the retrieval of more complete data sets from these screens. The concomitant increase of the size of the screens allows researchers to address new questions about the genes and signalling networks involved in tumour development. In addition, the development of new insertional mutagenesis tools such as DNA transposons enables screens for cancer genes in tissues that previously could not be analysed by retroviral insertional mutagenesis.
Asunto(s)
Mutagénesis Insercional/métodos , Neoplasias/genética , Animales , RatonesRESUMEN
Insertional mutagens such as viruses and transposons are a useful tool for performing forward genetic screens in mice to discover cancer genes. These screens are most effective when performed using hundreds of mice; however, until recently, the cost-effective isolation and sequencing of insertion sites has been a major limitation to performing screens on this scale. Here we present a method for the high-throughput isolation of insertion sites using a highly efficient splinkerette-PCR method coupled with capillary or 454 sequencing. This protocol includes a description of the procedure for DNA isolation, DNA digestion, linker or splinkerette ligation, primary and secondary PCR amplification, and sequencing. This method, which takes about 1 week to perform, has allowed us to isolate hundreds of thousands of insertion sites from mouse tumors and, unlike other methods, has been specifically optimized for the murine leukemia virus (MuLV), and can easily be performed in a 96-well plate format for the efficient multiplex isolation of insertion sites.
Asunto(s)
Virus de la Leucemia Murina/fisiología , Reacción en Cadena de la Polimerasa/métodos , Integración Viral , Animales , Electroforesis en Gel de Agar , Virus de la Leucemia Murina/genética , Ratones , Mutagénesis Insercional , Análisis de Secuencia de ADNRESUMEN
This article provides an overview of homelessness and mental health in New York City (NYC) over a recent period spanning from 1994 to 2006. This research was based on analysis of the main reports and studies on NYC homelessness and mental health and NYC Shelter System Register data. In 2006, the NYC homeless population was estimated at about 40,000 for any single day. Between 1994-2004, NYC shelters provided services to 416,720 individuals, including 163,438 children. The majority came from impoverished NYC areas. Many came from incarceration, streets and hospitals. Most were minority, particularly African-American. Homelessness had a major impact on morbidity and mortality. For 2001-2003, the HIV/AIDS estimated prevalence of the shelter population was twice that of the NYC adult population, and TB rate was 11 times higher. Two out of three of their hospitalizations were due to substance and alcohol use or mental illness (MI). Between 40-50 percent of single adults users are estimated to have a MI, however, the incidence over several years is much lower. A considerable number had a co-occurring MI and substance abuse history. Their death rate was twice that of the NYC population. Their leading deaths causes were heart disease, cancer, HIV/AIDS and substance abuse. NYC has developed the most extensive shelter service system for homeless people in the world. However, a crisis management approach, rather that addressing the roots of homelessness, has characterized its overall policy. Currently, there is a shift to an approach which seeks to drastically reduce homelessness in the next decade.
Este artigo forneceu uma visão geral da saúde mental da população de rua da cidade de Nova York (NY) no período de 1994 a 2006. O estudo baseou-se na análise dos principais relatórios e estudos sobre a saúde mental dessa população em NY, bem como o de sistemas de cadastro de abrigos da cidade. Em 2006, a população de rua atendida em abrigos de NY foi estimada em cerca de 40 mil pessoas em um único dia. Entre 1994-2004, tais abrigos prestaram serviços para 416.720 pessoas, destas, 163.438 eram crianças. A maioria da população era oriunda de áreas pobres, de encarceramento, de ruas e de hospitais; pertenciam principalmente a grupos de minorias étnicas como afrodescendentes. A população de rua representa um grande impacto na morbidade e mortalidade. Entre 2001-2003, a prevalência estimada do HIV/Aids na população dos abrigos e a taxa de tuberculose foram respectivamente o dobro e 11 vezes maior do que aquela encontrada na população adulta de NY. A maioria das internações nos abrigos (duas em cada três) decorreu do uso de substâncias, de álcool ou por doença mental; 40 a 50% são adultos solteiros e sofrem de transtorno mental. Um número considerável tinha uma comorbidade de transtorno mental e histórico de abuso de drogas. A taxa de mortalidade foi duas vezes maior que a taxa de mortalidade da população de NY. As principais causas de mortes foram: doenças cardíacas, câncer, HIV/Aids e abuso de substâncias. A cidade de Nova York desenvolveu um sistema de serviço de abrigo para moradores de rua mais amplo do mundo. Além de uma abordagem focada na gestão de crises que busca o enfrentamento das origens da falta de moradia, tem caracterizado a sua política geral com o objetivo de reduzir a população de rua na próxima década.