Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies.

BACKGROUND: Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility. METHODS: We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants. RESULTS: A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes. CONCLUSION: We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. IMPACT: Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer. Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk. Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.

The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023.

BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.

Rhabdomyosarcoma Associated with Core Myopathy/Malignant Hyperthermia: Combined Effect of Germline Variants in RYR1 and ASPSCR1 May Play a Role.

Rhabdomyosarcomas have been described in association with thyroid disease, dermatomyositis, Duchenne muscular dystrophy, and in muscular dystrophy models but not in patients with ryanodine receptor-1 gene (RYR1) pathogenic variants. We described here an 18-year-old male who reported a cervical nodule. Magnetic resonance images revealed a mass in the ethmoidal sinus corresponding to rhabdomyosarcoma. As his father died from malignant hyperthermia (MH), an in vitro contracture test was conducted and was positive for MH susceptibility. Muscle histopathological analysis in the biopsy showed the presence of cores. Molecular analysis using NGS sequencing identified germline variants in the RYR1 and ASPSCR1 (alveolar soft part sarcoma) genes. This report expands the spectrum of diseases associated with rhabdomyosarcomas and a possible differential diagnosis of soft tissue tumors in patients with RYR1 variants.

LHX6 promoter hypermethylation in oncological pediatric patients conceived by IVF.

The multifactorial etiology of pediatric cancer is poorly understood. Environmental factors occurring during embryogenesis can disrupt epigenetic signaling, resulting in several diseases after birth, including cancer. Associations between assisted reproductive technologies (ART), such as in vitro fertilization (IVF), and birth defects, imprinting disorders and other perinatal adverse events have been reported. IVF can result in methylation changes in the offspring, and a link with pediatric cancer has been suggested. In this study, we investigated the peripheral blood methylomes of 11 patients conceived by IVF who developed cancer in childhood. Methylation data of patients and paired sex/aged controls were obtained using the Infinium MethylationEPIC Kit (Illumina). We identified 25 differentially methylated regions (DMRs), 17 of them hypermethylated, and 8 hypomethylated in patients. The most significant DMR was a hypermethylated genomic segment located in the promoter region of LHX6, a transcription factor involved in the forebrain development and interneuron migration during embryogenesis. An additional control group was included to verify the LHX6 methylation status in children with similar cancers who were not conceived by ART. The higher LHX6 methylation levels in IVF patients compared to both control groups (healthy children and children conceived naturally who developed similar pediatric cancers), suggested that hypermethylation at the LHX6 promoter could be due to the IVF process and not secondary to the cancer itself. Further studies are required to evaluate this association and the potential role of LHX6 promoter hypermethylation for tumorigenesis.

Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Validação do Conteúdo de um Instrumento para Consulta de Enfermagem à Pessoa com Úlcera Venosa / Validation of the Content of an Instrument for Nursing Consultation for People With Venous Ulcer / Validación del Contenido de un Instrumento para Consulta de Enfermería para Personas con Úlcera Venosa

Objetivo:Validação do conteúdo de um instrumento para consulta de enfermagem à pessoa com úlcera venosa (UV). Metodologia: Estudo metodológico de validação interna de conteúdo baseado no julgamento de juízes estomaterapeutas, cuja identificação se deu através de busca na Plataforma Lattes. O processo ocorreu nos meses de janeiro e fevereiro de 2019 e 24 especialistas participaram. Os dados relativos à avaliação da consulta foram compilados em planilha do Microsoft Office Excel e considerados conforme índice de concordância (IC) total e global, totalizando 209 itens e 2.400 variáveis da consulta, sendo adotadas respostas dicotômicas. Resultados: Com relação à caracterização dos juízes, obteve-se idade média de 36,6 anos. A maioria foi do sexo feminino e localizada no estado do Ceará. A principal titulação observada foi o mestrado (62,5%) e os juízes atuavam na assistência e coordenação de serviço de estomaterapia. Dois terços apresentavam experiência com validação de instrumentos (66,7%). Com relação à validação da consulta, obteve-se um IC global de 92% e alfa de 0,91. Conclusão: A consulta possui aparência adequada para ser utilizada, é de fácil aplicação, possui sequência lógica, além de possibilitar um cuidado de enfermagem sistemático.

Objective:To validate the content of an instrument for nursing consultation with people with venous ulcers. Methodology:Methodological study of internal validation of content based on the judgment of enterostomal therapist judges, whose identification occurred through a search on the Lattes Platform. The process occurred in the months of January and February 2019 and 24 experts participated. Data regarding the evaluation of the query were compiled in Microsoft Office Excel spreadsheet and considered according to total and global agreement index, totaling 209 items and 2,400 variables of the query, dichotomous responses being adopted. Results: Regarding the characterization of the judges, a mean age of 36.6 years was obtained. Most were female and located in the state of Ceará. The main qualification observed was Master's degree (62.5%) and the judges worked in assistance and coordination of enterostomal therapy services. Two thirds had experience with validation of instruments (66.7%). Regarding the validation of the consultation, an overall agreement index of 92% and an alpha of 0.91 were obtained. Conclusion: The consultation has an adequate appearance to be used, is easy to apply, has a logical sequence, and enables a systematic nursing care.

Objetivo:Validación de contenido de un instrumento para consulta de enfermería a personas con úlceras venosas Metodología: Estudio metodológico de validación interna de contenido, a partir del juicio de jueces estomaterapeutas. Su identificación se dio a través de una búsqueda en la Plataforma Lattes que tuvieran experiencia en la atención de personas con úlceras venosas. El proceso se llevó a cabo en enero y febrero de 2019, donde participaron 24 expertos. Los datos relacionados a la evaluación de la consulta fueron recopilados en planilla de Microsoft Office Excel y analizados según el índice de concordancia total y global, totalizando 209 ítems y 2400 variables de consulta, siendo adoptadas respuestas dicotómicas. Resultados: En cuanto a la caracterización de los jueces se obtuvo una edad promedio de 36,6 años. La mayoría eran mujeres, así como del estado de Ceará. La principal titulación observada fue la de maestría, (62,5%) trabajaba en la asistencia y coordinación del servicio de estomaterapia. Dos tercios tenían experiencia con la validación de instrumentos (66,7%). En cuanto a la validación de la consulta se obtuvo un índice de acuerdo global del 92% y un alfa de 0,91. Conclusión: La consulta tiene una apariencia adecuada para ser utilizada, es fácil de aplicar, tiene una secuencia lógica, además de permitir una atención sistemática de enfermería.

Manejo da lesão por pressão em pacientes sob cuidados paliativos: visão dos enfermeiros / Management of pressure ulcers in palliative care patients: nurses' view

RESUMO Objetivo: compreender o manejo da lesão por pressão em pacientes sob cuidados paliativos na perspectiva de enfermeiros. Métodos: estudo qualitativo, do qual participaram 17 enfermeiros assistenciais por meio de entrevistas semiestruturadas. Os dados foram submetidos à análise categorial temática. Resultados: elencaram-se duas categorias: Manejo de enfermagem de lesões por pressão em pacientes sob cuidados paliativos e Desfecho das lesões por pressão em pacientes sob cuidados paliativos. O manejo destas ocorre por meio de assistência individualizada, podendo variar de acordo com os diferentes momentos em que àquele indivíduo se encontra, devendo ser maleáveis. Observou-se, ainda, a possibilidade de três desfechos: cicatrização completa, melhora clínica e estabilização clínica. Conclusão: apesar de toda fragilidade desses pacientes em cuidados paliativos, percebeu-se que ocorre a melhora clínica das lesões, apesar de ser um caminho lento, por meio de manejo das lesões de modo individualizado e centrado na busca de conforto.

ABSTRACT Objective: to understand the management of pressure ulcers in palliative care patients from the perspective of nurses. Methods: qualitative study, in which 17 care nurses participated through semi-structured interviews. Data were submitted to thematic categorical analysis. Results: two categories were listed: Nursing management of pressure ulcers in palliative care patients and Outcome of pressure ulcers in palliative care patients. Their management occurs by means of individualized assistance and may vary according to the different moments in which the individual is and should be malleable. The possibility of three outcomes was also observed: complete healing, clinical improvement and clinical stabilization. Conclusion: despite all the frailty of these patients in palliative care, it was perceived that the clinical improvement of the lesions occurs, although it is a slow path, by means of handling the lesions in an individualized manner and focused on the search for comfort.

Estágio extracurricular de Enfermagem: estratégia para a formação profissional / Extracurricular nursing internship: strategy for vocacional training

Objetivo: Verificar a influência do estágio extracurricular de Enfermagem para a formação profissional. Método: Pesquisa exploratória-descritiva, qualitativa. A coleta de dados ocorreu de abril a maio de 2018, por meio da aplicação de um formulário online a 19 egressos de um estágio extracurricular em enfermagem no setor de estomaterapia de um hospital de Fortaleza-CE. Resultados: Dezesseis egressos estavam trabalhando no período da coleta; quatorze conseguiram o primeiro emprego com menos de seis meses de graduação e possuíam alguma especialização. Apresentaram segurança, autonomia e habilidade técnica-científica, sentindo-se preparados para o exercício da profissão. Conclusão: Confirmou-se a existência de influência positiva das atividades extracurriculares sobre a formação profissional. O estágio extracurricular contemplou as exigências das Diretrizes Curriculares Nacionais do Curso de Graduação em Enfermagem e as do mercado de trabalho. (AU)

Objective: Know the contributions of the extracurricular nursing internship for the professional formation. Methodology: Exploratory-descriptive, qualitative research. Data collection took place from April to May 2018, through the application of an online form to 19 extracurricular nursing internship undergraduate in the stomatherapy sector of a Fortaleza-CE hospital. Results: Sixteen nursing students were already working at the data collection process time; fourteen had their first job with less than six months past their graduation process and had some specialization. They looked confident, presenting autonomy and technical-scientific skills. They also felt prepared for the future professional challenges. Conclusion: There was confirmation of the positive influence of extracurricular activities on professional training. The extracurricular internship covered the requirements of the National Curricular Guidelines of the Undergraduate Nursing Course and those of the labor market. (AU)

Objetivo: Conocer la influencia de la etapa extracurricular de Enfermería para la formación profesional. Método: Investigación exploratoria-descriptiva, cualitativa. La recolección de datos ocurrió de abril a mayo de 2018, por medio de la aplicación de un formulario on-line a 19 egresados de una etapa extracurricular en enfermería en el sector de estomaterapia de un hospital de Fortaleza-CE. Resultados: Dieciséis egresados estaban trabajando en el período de la recolección; catorce consiguieron el primer empleo con menos de seis meses de graduación y poseían alguna especialización. Ellos presentaron seguridad, autonomía y habilidad técnico-científica, sintiéndose preparados para el ejercicio de la profesión. Conclusión: Se confirmó la existencia de influencia positiva de las actividades extracurriculares sobre la formación profesional. La etapa extracurricular contempló las exigencias de las Directrices Curriculares Nacionales del Curso de Graduación en Enfermería y las del mercado de trabajo. (AU)