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1.
Am J Hum Genet ; 107(1): 72-82, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32504544

RESUMO

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.


Assuntos
Coleta de Dados/normas , Testes Genéticos/normas , Adulto , Criança , Grupos Étnicos , Feminino , Variação Genética/genética , Genômica/normas , Humanos , Masculino , Medicina de Precisão/normas , Inquéritos e Questionários
2.
Genome Med ; 12(1): 51, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471518

RESUMO

BACKGROUND: Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of diverse populations. METHODS: We conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas. Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups. We also identified the predisposition-associated two-hit events and gene expression effects in tumors. RESULTS: Genetic ancestry analysis classified the cohort of 9899 cancer cases into individuals of primarily European (N = 8184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N = 48, 0.5%), Native/Latin American (N = 41, 0.4%), and admixed (N = 11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) previously identified in Europeans, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma (OR = 8.5 [95% CI, 1.5-47.4]; FDR = 0.045). In the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR = 12.8 [95% CI, 1.8-90.8]; FDR = 0.038). Rare variant burden analysis further identified 7 suggestive associations in African ancestry individuals previously described in European ancestry, including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH. CONCLUSIONS: While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Studies using larger cohorts of diverse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies.

3.
Cancer ; 126(15): 3483-3492, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469081

RESUMO

BACKGROUND: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized. METHODS: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis. RESULTS: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05). CONCLUSIONS: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects. LAY SUMMARY: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable.

6.
Nature ; 577(7789): 179-189, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915397

RESUMO

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.


Assuntos
Variação Genética , Animais , Testes Genéticos , Genômica , Genótipo , Humanos , Fenótipo , Doenças Raras/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-31624068

RESUMO

Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.

8.
Blood Adv ; 3(20): 2962-2979, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648317

RESUMO

Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31645350

RESUMO

We describe the Clinical Genome Resource (ClinGen) cancer-related curation activities and the importance of curation to the evolving state of variant interpretation in a clinical context for both pediatric and adult cancer patients. We highlight specific examples from the CDH1 and PTEN Variant Curation Expert Panels (VCEPs) of the FDA-recognized process by which ClinGen VCEPs specify the American College of Medical Genetics and Genomics/Association of Molecular Pathology evidence code to develop variant classifications. We also review gene curations performed within the Hereditary Cancer Clinical Domain. We describe the parallel efforts for curation of somatic cancer variants from the Somatic Cancer Working Group. The ClinGen Germline/Somatic Committee is working to improve incorporation of both hereditary and somatic variant data to aid clinical interpretation. These ClinGen efforts rely on broad data sharing and detailed phenotypic and molecular information from published case studies to provide expert-curated variant interpretation to the cancer community.

10.
Proc Natl Acad Sci U S A ; 116(43): 21715-21726, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591222

RESUMO

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.


Assuntos
Proteínas Interatuantes com Canais de Kv/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular , Variações do Número de Cópias de DNA/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
11.
Am J Hum Genet ; 105(3): 625-630, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31303264

RESUMO

Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/genética , Subunidade Apc1 do Ciclossomo-Complexo Promotor de Anáfase/genética , Mutação , Síndrome de Rothmund-Thomson/genética , Humanos
12.
JAMA Oncol ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31219523

RESUMO

Importance: Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. Objectives: To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects. Design, Setting, and Participants: This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019. Exposures: Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries. Main Outcomes and Measures: Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk. Results: Compared with children without any birth defects (n = 10 181 074), children with chromosomal anomalies (n = 539 567) were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects (n = 2123) were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.4-6.5) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma. Conclusions and Relevance: Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

13.
Genet Med ; 21(12): 2791-2797, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31186522

RESUMO

PURPOSE: We describe parental perceptions of and experiences with genomic sequencing (GS) in the care of seriously ill children. Understanding parents' perspectives is vital for clinicians caring for children, given the uptake of genomic technologies into clinical practice. METHODS: Longitudinal, semistructured interviews were conducted with parents of pediatric cancer patients who underwent exome sequencing (ES) as a part of the BASIC3 study. Interviews were conducted at baseline, one to eight months after results disclosure, and approximately one year after disclosure. Using thematic qualitative analysis, parent interviews were coded with both inductive and deductive approaches. RESULTS: Before receiving genomic information, parents indicated that they saw ES as something responsible parents would agree to if their child had cancer. Some parents talked about the possibility of sequencing affecting feelings of culpability for their child's cancer, worrying that they passed on a cancer-causing gene or made parenting decisions that caused the disease. However, after receiving their child's ES results many reported feeling relieved of guilt and worry, and felt they had fulfilled parental duties by agreeing to ES for their child. CONCLUSION: These results reveal a layer of meaning that parents associate with GS that may inform clinicians' approach to care.


Assuntos
Testes Genéticos/ética , Poder Familiar/psicologia , Pais/psicologia , Adulto , Tomada de Decisões/ética , Revelação/ética , Feminino , Genômica , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Longitudinais , Masculino , Neoplasias/genética , Análise de Sequência , Comportamento Social , Responsabilidade Social
14.
Pediatr Blood Cancer ; 66(8): e27779, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31050187

RESUMO

Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Mutação , Neutropenia/patologia , Doenças do Sistema Nervoso Periférico/patologia , Telomerase/genética , Encurtamento do Telômero/genética , Adolescente , Adulto , Feminino , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Masculino , Neutropenia/induzido quimicamente , Neutropenia/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Prognóstico , Índice de Gravidade de Doença
15.
Annu Rev Genomics Hum Genet ; 20: 241-263, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31082280

RESUMO

Developments over the past five years have significantly advanced our ability to use genome-scale analyses-including high-density genotyping, transcriptome sequencing, exome sequencing, and genome sequencing-to identify the genetic basis of childhood cancer. This article reviews several key results from an expanding number of genomic studies of pediatric cancer: (a) Histopathologic subtypes of cancers can be associated with a high incidence of germline predisposition, (b) neurodevelopmental disorders or highly penetrant cancer predisposition syndromes can result from specific patterns of variation in genes encoding the SMARC family of chromatin remodelers, (c) genome-wide association studies with relatively small pediatric cancer cohorts have successfully identified single-nucleotide polymorphisms with large effect sizes and provided insight into population differences in cancer risk, and (d) multiple exome or genome analyses of unselected childhood cancer cohorts have yielded a 7-10% incidence of pathogenic variants in cancer predisposition genes. This work supports the increasing use of genomic sequencing in the care of pediatric cancer patients and at-risk family members.


Assuntos
Proteínas Cromossômicas não Histona/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Neoplasias/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adulto , Criança , Proteínas Cromossômicas não Histona/metabolismo , Exoma , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Mutação , Proteínas de Neoplasias/metabolismo , Neoplasias/classificação , Neoplasias/metabolismo , Neoplasias/patologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma
16.
Pediatr Blood Cancer ; 66(7): e27745, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30977242

RESUMO

BACKGROUND: Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC. PROCEDURE: To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non-FL-HCCs by sequencing a panel of cancer-associated genes and conducting copy-number and gene-expression analyses. RESULTS: We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican-3, another potential therapeutic target. CONCLUSION: Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non-FL-HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Sistema de Sinalização das MAP Quinases/genética , Mutação , Proteínas de Neoplasias/genética , Adolescente , Adulto , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Proteínas de Neoplasias/metabolismo
18.
Genet Med ; 21(2): 498-504, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29895853

RESUMO

Diagnostic genome-wide sequencing (exome or genome sequencing and data analysis for high-penetrance disease-causing variants) in acutely ill infants appears to be clinically useful, but the value of this diagnostic test should be rigorously demonstrated before it is accepted as a standard of care. This white paper was developed by the Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Work Stream to address the question of how we can determine the clinical value of genome-wide sequencing in infants in an intensive care setting. After reviewing available clinical and ethics literature on this question, we conclude that evaluating diagnostic genome-wide sequencing as a comprehensive scan for major genetic disease (rather than as a large panel of single-gene tests) provides a practical approach to assessing its clinical value in acutely ill infants. Comparing the clinical value of diagnostic genome-wide sequencing to chromosomal microarray analysis, the current evidence-based standard of care, per case of serious genetic disease diagnosed provides a practical means of assessing clinical value. Scientifically rigorous studies of this kind are needed to determine if clinical genome-wide sequencing should be established as a standard of care supported by healthcare systems and insurers for diagnosis of genetic disease in seriously ill newborn infants.


Assuntos
Testes Diagnósticos de Rotina , Testes Genéticos , Doenças do Recém-Nascido/genética , Terapia Intensiva Neonatal , Sequenciamento Completo do Genoma , Doença Aguda , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Penetrância
19.
Patient Educ Couns ; 102(4): 680-686, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30482469

RESUMO

OBJECTIVE: To examine communication patterns and behaviors during disclosure of exome sequencing (ES) results to parents of pediatric cancer patients, and describe common themes in parental communication. METHODS: Using mixed methods, we analyzed transcripts of sessions where parents of pediatric cancer patients received ES results from an oncologist and genetic counselor. Seventy-six transcripts were analyzed for frequency of clinician information-giving, partnering-supportive talk, and active parent participation. A subset of 40 transcripts were analyzed using thematic content analysis. RESULTS: Disclosures consisted mostly of clinician talk (84% of total talk), which was focused on providing information (62% of clinicians' utterances) with occasional partnering-supportive talk (7% of clinicians' utterances). Most parents assumed a passive, listening role (16% of total talk). Themes in parental communication included expressing relief and the significance of an answer, concern about sharing results and responsibility for inheritance, and seeking clarification of health implications of results. CONCLUSION: Our finding of low levels of active parent participation during ES disclosures highlights the need to improve patient/parent engagement and understanding in a genetic setting. PRACTICE IMPLICATIONS: Clinician communication strategies that could encourage parent participation and understanding include checking for parent understanding, partnership-building, and tailoring ES discussions to address parent concerns and preferences.


Assuntos
Comunicação , Revelação , Exoma/genética , Aconselhamento Genético , Neoplasias/genética , Oncologistas/psicologia , Pais/psicologia , Adulto , Criança , Tomada de Decisões , Humanos , Oncologia , Pessoa de Meia-Idade , Neoplasias/psicologia , Pacientes/psicologia , Relações Médico-Paciente , Médicos/psicologia , Relações Profissional-Família
20.
Genet Med ; 21(7): 1497-1506, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30504931

RESUMO

PURPOSE: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer. METHODS: Thirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed, or No Reported Evidence was assigned. RESULTS: Definitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer. CONCLUSION: Evaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health-care providers in interpreting results from panel testing.


Assuntos
Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos
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