RESUMEN
Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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Neoplasias Cerebelosas/metabolismo , Mutación de Línea Germinal , Meduloblastoma/metabolismo , Factores de Elongación Transcripcional/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Niño , Femenino , Humanos , Masculino , Meduloblastoma/genética , Linaje , ARN de Transferencia/metabolismo , Factores de Elongación Transcripcional/genéticaRESUMEN
Because germ line genetic testing is increasingly integrated into the clinical care of patients with hematologic malignancies, it is important for hematologists to effectively communicate with patients and their families about the genetic testing process and to relay the results in a concise and understandable manner. Effective communication facilitates trust between patients and providers and allows patients to feel empowered to ask questions and actively participate in their health care. Especially for inherited conditions, the patient's understanding of germ line genetic information is critical because it enables them to share this information with relatives who are at risk, thereby promoting cascade testing and providing potentially life-saving information to family members who may be similarly affected. Accordingly, a hematologist's skills in understanding the importance and implications of germ line genetic information and the ability to convey this information in patient-friendly language is a critical first step and can have a far-reaching impact. In this article, we outline a straightforward approach to discussing genetic information and provide the reader with practical tips that can be used when consenting patients to germ line genetic testing and disclosing subsequent test results. We also review special considerations and ethical concerns arising when offering genetic evaluation and germ line testing to patients and related donors for allogeneic hematopoietic stem cell transplantation.
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Pruebas Genéticas , Neoplasias Hematológicas , Humanos , Familia , Cuidados Paliativos , Células GerminativasRESUMEN
Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged <21 years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for the identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk variants in 28 pedigrees, of which 33 are coding and 11 are noncoding. The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5' untranslated region variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A>C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied.
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Enfermedad de Hodgkin , Humanos , Adulto Joven , Adulto , Enfermedad de Hodgkin/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Codón sin Sentido , Secuenciación Completa del Genoma , Linaje , Proteínas de Ciclo Celular/genéticaRESUMEN
The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Indenos/uso terapéutico , Paraganglioma/tratamiento farmacológico , Policitemia/tratamiento farmacológico , Adolescente , Neoplasias de las Glándulas Suprarrenales/genética , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores/sangre , Cromograninas/sangre , Femenino , Mutación con Ganancia de Función , Humanos , Indenos/efectos adversos , Imagen por Resonancia Magnética , Normetanefrina/sangre , Paraganglioma/genética , Policitemia/genética , Transducción de Señal , Síndrome , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.
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Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Células Germinativas , Consentimiento Informado/psicología , Competencia Mental/psicología , Neoplasias/genética , Padres/educación , Adolescente , Adulto , Anciano , Niño , Femenino , Mutación de Línea Germinal , Humanos , Conocimiento , Masculino , Persona de Mediana Edad , Autoinforme , Adulto JovenRESUMEN
OBJECTIVE: This study explores the experiences of adolescents and young adults with craniofacial microsomia, including the impact of growing up with this craniofacial condition on daily life and sense of self. The results may guide future research on optimally supporting individuals with craniofacial microsomia during this critical life phase. DESIGN AND SETTING: Participants were recruited through a craniofacial center, online patient support groups, and social media sites. Eleven individual semistructured interviews with participants between 12 and 22 years old were conducted by a single interviewer, transcribed, iteratively coded, and thematically analyzed. RESULTS: Five themes were evident in the data: (1) impact on personal growth and character development, (2) negative psychosocial impact, (3) deciding to hide or reveal the condition, (4) desire to make personal surgical decisions, and (5) struggles with hearing loss. CONCLUSIONS: We identified both medical and psychosocial concerns prevalent among adolescents with craniofacial microsomia. Although adolescents with craniofacial microsomia exhibit considerable resilience, the challenges they face impact their sense of self and should be addressed through psychosocial support and counseling. Further research should investigate the potential benefit of the wider use of hearing aids, as well as the involvement of patients in decision-making about reconstructive ear surgery.
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Síndrome de Goldenhar/psicología , Calidad de Vida , Actividades Cotidianas , Adolescente , Niño , Femenino , Humanos , Entrevistas como Asunto , Masculino , Investigación Cualitativa , Adulto JovenAsunto(s)
Codón sin Sentido , Anomalías Craneofaciales , Heterocigoto , Histona Acetiltransferasas/genética , Discapacidad Intelectual , Riñón/anomalías , Rótula/anomalías , Trastornos Psicomotores , Escroto/anomalías , Tomografía Computarizada por Rayos X , Anomalías Urogenitales , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Anomalías Craneofaciales/cirugía , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/cirugía , Riñón/diagnóstico por imagen , Riñón/patología , Riñón/cirugía , Masculino , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/genética , Neuroblastoma/patología , Neuroblastoma/cirugía , Rótula/diagnóstico por imagen , Rótula/patología , Rótula/cirugía , Trastornos Psicomotores/diagnóstico por imagen , Trastornos Psicomotores/genética , Trastornos Psicomotores/patología , Trastornos Psicomotores/cirugía , Escroto/diagnóstico por imagen , Escroto/patología , Escroto/cirugía , Anomalías Urogenitales/diagnóstico por imagen , Anomalías Urogenitales/genética , Anomalías Urogenitales/patología , Anomalías Urogenitales/cirugíaRESUMEN
PURPOSE: To characterize parents' quality of life (QoL) after germline genomic sequencing for their children with cancer. METHODS: Participants were n = 104 parents of children with cancer enrolled in a prospective study of clinical tumor and germline genomic sequencing. Parents completed surveys at study consent (T0), before disclosure of their child's germline results (T1), and again ≥5 weeks after results disclosure (T2). Bivariate associations with QoL were examined, followed by a multivariable regression model predicting parents' psychological distress. RESULTS: At T2, parental distress significantly differed by their children's germline result type (positive, uncertain, negative; P = .038), parent relationship status (P = .04), predisclosure genetics knowledge (P = .006), and predisclosure worry about sequencing (P < .001). Specifically, parents of children with positive (ie, pathogenic or likely pathogenic) results experienced greater distress than those of children with negative results (P = .029), as did parents who were single, more knowledgeable about genetics, and with greater worry. In the adjusted regression model, a positive germline result remained significantly associated with parents' lower QoL at T2 follow-up (F [4,92] = 9.95; P < .001; R2 = .30; ß = .19; P = .031). CONCLUSION: Germline genomic sequencing for children with cancer is associated with distress among parents when revealing an underlying cancer predisposition among their affected children. Genetic education and counseling before and after germline sequencing may help attenuate this impact on QoL by addressing parents' concerns about test results and their health implications. Assessing parents' worry early in the testing process may also aid in identifying those most likely in need of psychosocial support.
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Neoplasias , Calidad de Vida , Niño , Humanos , Calidad de Vida/psicología , Revelación , Estudios Prospectivos , Padres/psicología , Neoplasias/genética , Células GerminativasRESUMEN
Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.
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Neoplasias , Niño , ADN , Humanos , Mutación , Neoplasias/genética , Análisis de Secuencia de ARN , Secuenciación del ExomaRESUMEN
PURPOSE: For the advances of pediatric oncology next generation sequencing (NGS) research to equitably benefit all children, a diverse and representative sample of participants is needed. However, little is known about demographic and clinical characteristics that differentiate families who decline enrollment in pediatric oncology NGS research. METHODS: Demographic and clinical data were retrospectively extracted for 363 pediatric oncology patients (0-21 years) approached for enrollment on Genomes for Kids (G4K), a study examining the feasibility of comprehensive clinical genomic analysis of tumors and paired normal samples. Demographic and clinical factors that significantly differentiated which families declined were subsequently compared to enrollment in Clinical Implementation of Pharmacogenetics (PG4KDS) for 348 families, a pharmacogenomics study with more explicit therapeutic benefit examining genes affecting drug responses and metabolism. RESULTS: Fifty-three (14.6%) families declined enrollment in G4K. Race/ethnicity was the only variable that significantly differentiated study refusal using multivariate logistic regression, with families of black children more likely to decline enrollment compared to families of non-Hispanic or Hispanic white children. Reasons for declining G4K were generally consistent with other pediatric genomics research, with feeling overwhelmed and insurance discrimination fears most frequently cited. Families of black children were also more likely to decline enrollment in PG4KDS. Thirteen (3.7%) of the 348 families approached for both studies declined PG4KDS. CONCLUSION: Race/ethnicity differentiated study declination across two different pediatric oncology genomics studies, suggesting enrollment disparities in the context of pediatric oncology genomics research. Genomics research participant samples that do not fully represent racial and ethnic minorities risk further exacerbating health disparities. Additional work is needed to understand the nuances of parental decision making in genomic research and facilitate enrollment of diverse patient populations.
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Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.
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Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund-Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9-17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.
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Osteosarcoma/genética , RecQ Helicasas/genética , Adolescente , Niño , Femenino , Células Germinativas , Humanos , Mutación con Pérdida de Función/genética , Pérdida de Heterocigocidad/genética , Masculino , Mutación , Osteosarcoma/metabolismo , Linaje , RecQ Helicasas/metabolismoRESUMEN
INTRODUCTION: The advent of next-generation sequencing (NGS) has introduced an exciting new era in biomedical research. NGS forms the foundation of current genetic testing approaches, including targeted gene panel testing, as well as more comprehensive whole-exome and whole-genome sequencing. Together, these approaches promise to provide critical insights into the understanding of health and disease. However, with NGS testing come many ethical questions and concerns, particularly when testing involves children. These concerns are especially relevant for children with cancer, where the testing of tumor and germline tissues is increasingly being incorporated into clinical care. Areas covered: In this manuscript, we explore the key ethical considerations related to conducting germline NGS testing in pediatric oncology, focusing on the four main principles of beneficence, non-maleficence, autonomy and justice. Expert commentary: The ethical issues surrounding germline NGS testing are complex and result in part from our limited understanding of the medical relevance of many of the results obtained and poor knowledge of the impacts of testing, both beneficial and detrimental, on patients and their families. In this article we discuss the risks and benefits of germline NGS testing and the arguments for and against such testing in children with cancer.