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PURPOSE: To estimate the absolute number of adult survivors of childhood cancer in the U.S. population who carry a pathogenic or likely pathogenic variant in a cancer predisposition gene. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated the number of childhood cancer survivors on December 31, 2016 for each childhood cancer diagnosis, multiplied this by the proportion of carriers of pathogenic/likely pathogenic variants in the St. Jude Lifetime Cohort (SJLIFE) study, and projected the resulting number onto the U.S. RESULTS: Based on genome sequence data, 11.8% of 2450 SJLIFE participants carry a pathogenic/likely pathogenic variant in one of 156 cancer predisposition genes. Given this information, we estimate that 21 800 adult survivors of childhood cancer in the United States carry a pathogenic/likely pathogenic variant in one of these genes. The highest estimated absolute number of variant carriers are among survivors of central nervous system tumors (n = 4300), particularly astrocytoma (n = 1800) and other gliomas (n = 1700), acute lymphoblastic leukemia (n = 4300), and retinoblastoma (n = 3500). The most frequently mutated genes are RB1 (n = 3000), NF1 (n = 2300), and BRCA2 (n = 800). CONCLUSION: Given the increasing number of childhood cancer survivors in the United States, clinicians should counsel survivors regarding their potential genetic risk, consider referral for genetic counseling and testing, and, as appropriate, implement syndrome-specific cancer surveillance or risk-reducing measures.
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Supervivientes de Cáncer/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Proteínas de Neoplasias/genética , Neoplasias/mortalidad , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/genética , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
The gray wolf (Canis lupus) is a widely distributed top predator and ancestor of the domestic dog. To address questions about wolf relationships to each other and dogs, we assembled and analyzed a data set of 34 canine genomes. The divergence between New and Old World wolves is the earliest branching event and is followed by the divergence of Old World wolves and dogs, confirming that the dog was domesticated in the Old World. However, no single wolf population is more closely related to dogs, supporting the hypothesis that dogs were derived from an extinct wolf population. All extant wolves have a surprisingly recent common ancestry and experienced a dramatic population decline beginning at least â¼30 thousand years ago (kya). We suggest this crisis was related to the colonization of Eurasia by modern human hunter-gatherers, who competed with wolves for limited prey but also domesticated them, leading to a compensatory population expansion of dogs. We found extensive admixture between dogs and wolves, with up to 25% of Eurasian wolf genomes showing signs of dog ancestry. Dogs have influenced the recent history of wolves through admixture and vice versa, potentially enhancing adaptation. Simple scenarios of dog domestication are confounded by admixture, and studies that do not take admixture into account with specific demographic models are problematic.
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Perros/genética , Lobos/genética , Animales , Teorema de Bayes , ADN Mitocondrial/genética , Femenino , Genoma , Hibridación Genética , Masculino , Cadenas de Markov , Modelos Genéticos , Filogenia , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Análisis de Secuencia de ADNRESUMEN
Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.
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Neoplasias Encefálicas/diagnóstico , Encéfalo/patología , Glioblastoma/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Genómica , Glioblastoma/diagnóstico , Glioma/genética , Humanos , Masculino , Mutación/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , RecurrenciaRESUMEN
BACKGROUND: The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS: In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS: Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS: Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).
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Genes Relacionados con las Neoplasias , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias/genética , Adolescente , Trastorno Autístico/genética , Niño , Femenino , Genes Dominantes , Genoma Humano , Humanos , Masculino , Programa de VERF , Análisis de Secuencia de ADN/métodos , Adulto JovenRESUMEN
The emergence of human infection with a novel H7N9 influenza virus in China raises a pandemic concern. Chicken H9N2 viruses provided all six of the novel reassortant's internal genes. However, it is not fully understood how the prevalence and evolution of these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that over more than 10 y of cocirculation of multiple H9N2 genotypes, a genotype (G57) emerged that had changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens in China, caused widespread outbreaks in 2010-2013 before the H7N9 viruses emerged in humans, and finally provided all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.
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Pollos/virología , Evolución Molecular , Subtipo H7N9 del Virus de la Influenza A/genética , Subtipo H9N2 del Virus de la Influenza A/genética , Animales , Variación Antigénica/genética , Antígenos Virales/genética , China/epidemiología , Genes Virales , Flujo Genético , Genotipo , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Subtipo H7N9 del Virus de la Influenza A/inmunología , Subtipo H7N9 del Virus de la Influenza A/patogenicidad , Subtipo H9N2 del Virus de la Influenza A/inmunología , Subtipo H9N2 del Virus de la Influenza A/patogenicidad , Gripe Aviar/epidemiología , Gripe Aviar/virología , Gripe Humana/epidemiología , Gripe Humana/virología , Pandemias , Filogenia , Virus Reordenados/genética , Virus Reordenados/inmunología , Virus Reordenados/patogenicidad , Estudios RetrospectivosRESUMEN
BACKGROUND: The cost of Whole Genome Sequencing (WGS) has decreased tremendously in recent years due to advances in next-generation sequencing technologies. Nevertheless, the cost of carrying out large-scale cohort studies using WGS is still daunting. Past simulation studies with coverage at ~2x have shown promise for using low coverage WGS in studies focused on variant discovery, association study replications, and population genomics characterization. However, the performance of low coverage WGS in populations with a complex history and no reference panel remains to be determined. RESULTS: South Indian populations are known to have a complex population structure and are an example of a major population group that lacks adequate reference panels. To test the performance of extremely low-coverage WGS (EXL-WGS) in populations with a complex history and to provide a reference resource for South Indian populations, we performed EXL-WGS on 185 South Indian individuals from eight populations to ~1.6x coverage. Using two variant discovery pipelines, SNPTools and GATK, we generated a consensus call set that has ~90% sensitivity for identifying common variants (minor allele frequency ≥ 10%). Imputation further improves the sensitivity of our call set. In addition, we obtained high-coverage for the whole mitochondrial genome to infer the maternal lineage evolutionary history of the Indian samples. CONCLUSIONS: Overall, we demonstrate that EXL-WGS with imputation can be a valuable study design for variant discovery with a dramatically lower cost than standard WGS, even in populations with a complex history and without available reference data. In addition, the South Indian EXL-WGS data generated in this study will provide a valuable resource for future Indian genomic studies.
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Pueblo Asiatico/genética , Metagenómica , Secuenciación Completa del Genoma , Variación Genética , Genoma Mitocondrial/genética , HumanosRESUMEN
Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.
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Neoplasias Encefálicas/patología , Genes myb , Predisposición Genética a la Enfermedad , Glioma/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Niño , Preescolar , Proteínas de Unión al ADN , Femenino , Ganglioglioma/genética , Ganglioglioma/patología , Glioma/patología , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ARN , Transactivadores/genética , Factores de Transcripción , Adulto JovenRESUMEN
BACKGROUND: Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. METHODS: Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL. FINDINGS: We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050). INTERPRETATION: Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed. FUNDING: US National Institutes of Health and American Lebanese Syrian Associated Charities.
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Biomarcadores de Tumor/genética , Mutación de Línea Germinal , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Adolescente , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Biología Computacional , Análisis Mutacional de ADN , Bases de Datos Genéticas , Exoma , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Cariotipificación , Masculino , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Factores de Riesgo , Resultado del Tratamiento , Proteína ETS de Variante de Translocación 6RESUMEN
CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project (http://browser.1000genomes.org/index.html) indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19*2, but found alone on CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 and rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*1/*35 heterozygous alleles. Extended haplotype homozygosity tests of the HapMap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19*35 and CYP2C19*2) are under significant natural selection, with CYP2C19*35 having a higher relative extended haplotype homozygosity score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19*35 and that rs4244285 was added later, creating CYP2C19*2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19*35 and CYP2C19*2 alleles in liver.
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Citocromo P-450 CYP2C19/genética , Hígado/enzimología , Acetilación , Adulto , Alelos , Citocromo P-450 CYP2C19/metabolismo , ADN Complementario/biosíntesis , ADN Complementario/genética , Etiopía/epidemiología , Exones , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Mefenitoína/farmacocinética , Fenotipo , Filogenia , Polimorfismo de Nucleótido Simple , Empalme del ARN , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Piwi-interacting RNAs (piRNAs) are a recently discovered class of small non-coding RNAs whose best-understood function is to repress mobile element (ME) activity in animal germline. To date, nearly all piRNA studies have been conducted in model organisms and little is known about piRNA diversity, target specificity and biological function in human. RESULTS: Here we performed high-throughput sequencing of piRNAs from three human adult testis samples. We found that more than 81% of the ~17 million putative piRNAs mapped to ~6,000 piRNA-producing genomic clusters using a relaxed definition of clusters. A set of human protein-coding genes produces a relatively large amount of putative piRNAs from their 3'UTRs, and are significantly enriched for certain biological processes, suggestive of non-random sampling by the piRNA biogenesis machinery. Up to 16% of putative piRNAs mapped to a few hundred annotated long non-coding RNA (lncRNA) genes, suggesting that some lncRNA genes can act as piRNA precursors. Among major ME families, young families of LTR and endogenous retroviruses have a greater association with putative piRNAs than other MEs. In addition, piRNAs preferentially mapped to specific regions in the consensus sequences of several ME (sub)families and some piRNA mapping peaks showed patterns consistent with the "ping-pong" cycle of piRNA targeting and amplification. CONCLUSIONS: Overall our data provide a comprehensive analysis and improved annotation of human piRNAs in adult human testes and shed new light into the relationship of piRNAs with protein-coding genes, lncRNAs, and mobile genetic elements in human.
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ARN Interferente Pequeño/metabolismo , Testículo/metabolismo , Transcriptoma , Regiones no Traducidas 3' , Adulto , Secuencia de Bases , Mapeo Cromosómico , Secuencia de Consenso , Ontología de Genes , Humanos , Masculino , Familia de Multigenes , Interferencia de ARN , ARN Largo no Codificante , ARN Interferente Pequeño/genética , Retroelementos , Análisis de Secuencia de ARNRESUMEN
Highly efficient synthesis of enantiomerically enriched substituted piperidines has been realized via chiral phosphoric acid catalyzed cascade hydrogenative dearomatization of substituted pyridines and aza-Friedel-Crafts reaction in good to excellent yields and enantioselectivity.
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Compuestos Aza/química , Piridinas/química , Alquilación , Catálisis , Hidrogenación , Metales/química , Oxidación-Reducción , Ácidos Fosfóricos , EstereoisomerismoRESUMEN
Phase-resetting properties of neurons determine their functionality as integrators (type 1) vs. resonators (type 2), as well as their synchronization tendencies. We introduce a novel, bias-correction method to estimate the infinitesimal phase-resetting curve (iPRC) and confirm type 1 excitability in hippocampal pyramidal CA1 neurons in vitro by two independent methods. First, PRCs evoked using depolarizing pulses consisted only of advances, consistent with type 1. Second, the frequency/current (f/I) plots showed no minimum frequency, again consistent with type 1. Type 1 excitability was also confirmed by the absence of a resonant peak in the interspike interval histograms derived from the f/I data. The PRC bias correction assumed that the distribution of noisy phase resetting is truncated, because an input cannot advance a spike to a point in time before the input (the causal limit) and successfully removed the statistical bias for delays in the null PRC in response to zero-magnitude input by computing the phase resetting as the mean of the untruncated distribution. The PRC for depolarization peaked at late phases and decreased to zero by the end of the cycle, whereas delays observed in response to hyperpolarization increased monotonically. The bias correction did not affect this difference in shape, which was due instead to the causal limit obscuring the iPRC for depolarization but not hyperpolarization. Our results suggest that weak periodic hyperpolarizing drive can theoretically entrain CA1 pyramidal neurons at any phase but that strong excitation will preferentially phase-lock them with zero time lag.
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Potenciales de Acción , Región CA1 Hipocampal/fisiología , Células Piramidales/fisiología , Animales , Región CA1 Hipocampal/citología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a network period that cause each neuron to receive an input late in its firing cycle and almost immediately fire an action potential. Synchronization for these long delays was surprisingly tight and robust to the noise and heterogeneity inherent in a biological system. In contrast to excitatory coupling, inhibitory coupling led to antiphase for no delay, very short delays and delays close to a network period, but to near-synchrony for a wide range of relatively short delays. PRC-based methods show that conduction delays can stabilize synchrony in several ways, including neutralizing a discontinuity introduced by strong inhibition, favoring synchrony in the case of noisy bistability, and avoiding an initial destabilizing region of a weakly type II PRC. PRCs can identify optimal conduction delays favoring synchronization at a given frequency, and also predict robustness to noise and heterogeneity.
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Relojes Biológicos/fisiología , Corteza Entorrinal/fisiología , Modelos Neurológicos , Red Nerviosa/fisiología , Conducción Nerviosa/fisiología , Inhibición Neural/fisiología , Transmisión Sináptica/fisiología , Animales , Simulación por Computador , Potenciales Postsinápticos Excitadores/fisiología , HumanosRESUMEN
PURPOSE: Copy-number (CN) features reveal the molecular state of cancers and may have predictive and prognostic value in the treatment of cancer. We sought to apply published CN analysis methods to a large pan-cancer data set and characterize ubiquitous CN signatures across tumor types, including potential utility for treatment selection. METHODS: We analyzed the landscape of CN features in 260,333 pan-cancer samples. We examined the association of 10 signatures with genomic alterations and clinical characteristics and trained a machine learning classifier using CN and insertion and deletion features to detect homologous recombination deficiency signature (HRDsig) positivity. Clinical outcomes were assessed using a real-world clinicogenomic database (CGDB) of comprehensive genomic profiling linked to deidentified, electronic health record-derived clinical data. RESULTS: CN signatures were prevalent across cancer types and associated with diverse processes including focal tandem duplications, seismic amplifications, genome-wide loss of heterozygosity (gLOH), and HRD. Our novel HRDsig outperformed gLOH in predicting BRCAness and effectively distinguished biallelic BRCA and homologous recombination-repair wild-type (HRRwt) samples pan-tumor, demonstrating high sensitivity to detect biallelic BRCA in ovarian (93%) and other HRD-associated cancers (80%-87%). Pan-tumor prevalence of HRDsig was 6.4%. HRRwt cases represented a significant fraction of the HRDsig-positive cohort, likely reflecting a population with nongenomic mechanisms of HRD. In ovarian and prostate CGDBs, HRDsig identified more patients than gLOH and had predictive value for poly (ADP-ribose) polymerase inhibitor (PARPi) benefit. CONCLUSION: Tumor CN profiles are informative, revealing diverse processes active in cancer. We describe the landscape of 10 CN signatures in a large pan-cancer cohort, including two associated with HRD. We trained a machine learning-based HRDsig that robustly identified BRCAness and associated with biallelic BRCA pan-tumor, and was predictive of PARPi benefit in real-world ovarian and prostate data sets.
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Antineoplásicos , Neoplasias Ováricas , Masculino , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ribosa/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Antineoplásicos/uso terapéutico , Reparación del ADN por Recombinación , BiomarcadoresRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Multiómica , Receptor ErbB-2/genética , Receptor ErbB-2/análisis , Receptor ErbB-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores de Estrógenos/genética , Receptores de Estrógenos/análisis , Receptores de Estrógenos/uso terapéutico , Estrógenos/uso terapéuticoRESUMEN
Sequencing cases without matched healthy controls hinders prioritization of germline disease-predisposition genes. To circumvent this problem, genotype summary counts from public data sets can serve as controls. However, systematic inflation and false positives can arise if confounding factors are not controlled. We propose a framework, consistent summary counts based rare variant burden test (CoCoRV), to address these challenges. CoCoRV implements consistent variant quality control and filtering, ethnicity-stratified rare variant association test, accurate estimation of inflation factors, powerful FDR control, and detection of rare variant pairs in high linkage disequilibrium. When we applied CoCoRV to pediatric cancer cohorts, the top genes identified were cancer-predisposition genes. We also applied CoCoRV to identify disease-predisposition genes in adult brain tumors and amyotrophic lateral sclerosis. Given that potential confounding factors were well controlled after applying the framework, CoCoRV provides a cost-effective solution to prioritizing disease-risk genes enriched with rare pathogenic variants.
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Esclerosis Amiotrófica Lateral , Neoplasias , Adulto , Esclerosis Amiotrófica Lateral/genética , Niño , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias/genéticaRESUMEN
Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSß0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the ß-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.
Asunto(s)
Anemia de Células Falciformes , Hemoglobina Fetal , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Niño , Hemoglobina Fetal/genética , Humanos , Estudios Longitudinales , Dolor , Polimorfismo de Nucleótido SimpleRESUMEN
Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community.This article is highlighted in the In This Issue feature, p. 995.
Asunto(s)
Anemia de Células Falciformes/genética , Nube Computacional , Genómica , Difusión de la Información , Neoplasias/genética , Niño , Ecosistema , Hospitales Pediátricos , HumanosRESUMEN
To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.
Asunto(s)
Antígeno B7-H1/genética , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Terapia Neoadyuvante/métodos , Antraciclinas/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/mortalidad , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel/uso terapéutico , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Estudios Longitudinales , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Neoplasia Residual , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent. Through interrogation of single-nucleotide polymorphisms (SNPs) in the WGS data, we unequivocally prove that the MDS is donor-derived. Additionally, we sequenced 15 samples from 12 time points, including the initial B-ALL diagnostic sample through several post-HCT remission samples, the dMDS, and representative germline samples from both patient and donor, to show that the MDS-related pathologic mutations, including a canonical ASXL1 (p.Y700*) mutation, were detectable nearly 3 yr prior to the morphological detection of MDS. Furthermore, these MDS mutations were not detectable immediately following, and for >1 yr post-, HCT. These data support the clinical utility of comprehensive sequencing following HCT to detect donor-derived malignancies, while providing insights into the clonal progression of dMDS over a 4-yr period.