RESUMO
Digital health solutions, with apps, virtual care, and electronic medical records, are gaining momentum across all medical disciplines, and their adoption has been accelerated, in part, by the COVID-19 pandemic. Personal wearables, sensors, and mobile technologies are increasingly being used to identify health risks and assist in diagnosis, treatment, and monitoring of health and disease. Genomics is a vanguard of digital healthcare as we witness a convergence of the fields of genomic and digital medicine. Spurred by the acute need to increase health literacy, empower patients' preference-sensitive decisions, or integrate vast amounts of complex genomic data into the clinical workflow, there has been an emergence of digital support tools in genomics-enabled care. We present three use cases that demonstrate the application of these converging technologies: digital genomics decision support tools, conversational chatbots to scale the genetic counseling process, and the digital delivery of comprehensive genetic services. These digital solutions are important to facilitate patient-centered care delivery, improve patient outcomes, and increase healthcare efficiencies in genomic medicine. Yet the development of these innovative digital genomic technologies also reveals strategic challenges that need to be addressed before genomic digital health can be broadly adopted. Alongside key evidentiary gaps in clinical and cost-effectiveness, there is a paucity of clinical guidelines, policy, and regulatory frameworks that incorporate digital health. We propose a research agenda, guided by learning healthcare systems, to realize the vision of digital health-enabled genomics to ensure its sustainable and equitable deployment in clinical care.
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COVID-19 , Pandemias , COVID-19/genética , Atenção à Saúde , Registros Eletrônicos de Saúde , Genômica , HumanosRESUMO
BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).
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Carcinoma Ductal Pancreático , Predisposição Genética para Doença , Testes Genéticos , Neoplasias Pancreáticas , Medidas de Resultados Relatados pelo Paciente , Telemedicina , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/psicologia , Neoplasias Pancreáticas/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/psicologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Predisposição Genética para Doença/psicologia , Medição de Risco , Idoso , Ansiedade/psicologia , Ansiedade/diagnóstico , Ansiedade/etiologia , Adulto , Depressão/diagnóstico , Depressão/genética , Depressão/psicologia , Aconselhamento Genético/psicologia , Mutação em Linhagem Germinativa , Família/psicologiaRESUMO
Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan.
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COVID-19/epidemiologia , Pandemias , SARS-CoV-2 , Instituições Acadêmicas , COVID-19/prevenção & controle , COVID-19/transmissão , COVID-19/virologia , Humanos , Modelos Teóricos , Distanciamento Físico , Vigilância da População , Prevalência , Estudantes , VacinaçãoRESUMO
The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.
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Células Epiteliais/citologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Humanas/citologia , Células-Tronco/citologia , Células-Tronco Adultas/citologia , Animais , Antígeno CD24/metabolismo , Transformação Celular Neoplásica , Células Cultivadas , Humanos , Receptores de Hialuronatos/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Células-Tronco Neoplásicas/citologia , Esferoides Celulares , Células Tumorais CultivadasRESUMO
Advances in genome sequencing have led to a tremendous increase in the discovery of novel missense variants, but evidence for determining clinical significance can be limited or conflicting. Here, we present Learning from Evidence to Assess Pathogenicity (LEAP), a machine learning model that utilizes a variety of feature categories to classify variants, and achieves high performance in multiple genes and different health conditions. Feature categories include functional predictions, splice predictions, population frequencies, conservation scores, protein domain data, and clinical observation data such as personal and family history and covariant information. L2-regularized logistic regression and random forest classification models were trained on missense variants detected and classified during the course of routine clinical testing at Color Genomics (14,226 variants from 24 cancer-related genes and 5,398 variants from 30 cardiovascular-related genes). Using 10-fold cross-validated predictions, the logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 97.8% (cancer) and 98.8% (cardiovascular), while the random forest model achieved 98.3% (cancer) and 98.6% (cardiovascular). We demonstrate generalizability to different genes by validating predictions on genes withheld from training (96.8% AUROC). High accuracy and broad applicability make LEAP effective in the clinical setting as a high-throughput quality control layer.
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Genômica/métodos , Aprendizado de Máquina , Modelos Genéticos , Mutação de Sentido Incorreto , Área Sob a Curva , Doenças Cardiovasculares/genética , Humanos , Modelos Logísticos , Modelos Estatísticos , Neoplasias/genética , Curva ROCRESUMO
BACKGROUND: Next generation sequencing (NGS) has become a common technology for clinical genetic tests. The quality of NGS calls varies widely and is influenced by features like reference sequence characteristics, read depth, and mapping accuracy. With recent advances in NGS technology and software tools, the majority of variants called using NGS alone are in fact accurate and reliable. However, a small subset of difficult-to-call variants that still do require orthogonal confirmation exist. For this reason, many clinical laboratories confirm NGS results using orthogonal technologies such as Sanger sequencing. Here, we report the development of a deterministic machine-learning-based model to differentiate between these two types of variant calls: those that do not require confirmation using an orthogonal technology (high confidence), and those that require additional quality testing (low confidence). This approach allows reliable NGS-based calling in a clinical setting by identifying the few important variant calls that require orthogonal confirmation. RESULTS: We developed and tested the model using a set of 7179 variants identified by a targeted NGS panel and re-tested by Sanger sequencing. The model incorporated several signals of sequence characteristics and call quality to determine if a variant was identified at high or low confidence. The model was tuned to eliminate false positives, defined as variants that were called by NGS but not confirmed by Sanger sequencing. The model achieved very high accuracy: 99.4% (95% confidence interval: +/- 0.03%). It categorized 92.2% (6622/7179) of the variants as high confidence, and 100% of these were confirmed to be present by Sanger sequencing. Among the variants that were categorized as low confidence, defined as NGS calls of low quality that are likely to be artifacts, 92.1% (513/557) were found to be not present by Sanger sequencing. CONCLUSIONS: This work shows that NGS data contains sufficient characteristics for a machine-learning-based model to differentiate low from high confidence variants. Additionally, it reveals the importance of incorporating site-specific features as well as variant call features in such a model.
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Sequenciamento de Nucleotídeos em Larga Escala , Aprendizado de Máquina , Modelos Estatísticos , Sequência de Bases , Variação GenéticaRESUMO
Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk.
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Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único/genética , Processamento Alternativo/genética , Teorema de Bayes , Linhagem Celular , Predisposição Genética para Doença/genética , Humanos , Isoformas de Proteínas/genética , Locos de Características Quantitativas/genéticaRESUMO
PURPOSE: The contribution of genetic factors to cancer in non-Jewish populations in Israel is understudied. Yet the early, mostly premenopausal age at breast cancer diagnosis is suggestive of an inherited predisposition. METHODS: High-risk cancer cases of non-Jewish origin who were counseled at the Oncogenetics unit, Sheba Medical Center and the oncology institute at the Ziv medical center from January 1, 2000 to December 31 2016 were eligible. DNA extracted from leukocytes was subjected to massive parallel, next-generation sequencing using the Color Genomics platform. Data were analyzed for pathogenic and likely pathogenic mutations using existing pipelines. RESULTS: Overall, 68 cases, each representing a unique high-risk breast/ovarian family, were genotyped: 32 Druze, 26 Muslim Arabs, and 10 Christian Arabs. Fifty-nine had breast cancer (mean age at diagnosis 42.7 ± 7.6 years), and 9 had ovarian cancer (51.6 ± 9.7 years). Overall three pathogenic mutations one each in BRCA1, PALB2, and BRIP1 genes were detected mostly in Druze families. In addition, 29 variants of unknown significance were also detected, and in 36 cases no sequence variants were noted in any of the genotyped genes. CONCLUSION: The contribution of the known cancer susceptibility genes to the burden of inherited breast/ovarian cancer predisposition in non-Jews in Israel is modest. Other genes or molecular mechanisms account for the familial breast/ovarian cancer clustering in this population.
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Neoplasias da Mama/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Árabes/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Israel/epidemiologia , Judeus/genética , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologiaRESUMO
The noncanonical IKK family member IKKepsilon is essential for regulating antiviral signaling pathways and is a recently discovered breast cancer oncoprotein. Although several IKKepsilon targets have been described, direct IKKepsilon substrates necessary for regulating cell transformation have not been identified. Here, we performed a screen for putative IKKepsilon substrates using an unbiased proteomic and bioinformatic approach. Using a positional scanning peptide library assay, we determined the optimal phosphorylation motif for IKKepsilon and used bioinformatic approaches to predict IKKepsilon substrates. Of these potential substrates, serine 418 of the tumor suppressor CYLD was identified as a likely site of IKKepsilon phosphorylation. We confirmed that CYLD is directly phosphorylated by IKKepsilon and that IKKepsilon phosphorylates serine 418 in vivo. Phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKKepsilon-driven transformation. Together, these observations define IKKepsilon and CYLD as an oncogene-tumor suppressor network that participates in tumorigenesis.
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Neoplasias da Mama , Transformação Celular Neoplásica , Quinase I-kappa B/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Enzima Desubiquitinante CYLD , Feminino , Genes Reporter , Humanos , Quinase I-kappa B/genética , Dados de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação , Alinhamento de Sequência , Serina/metabolismo , Especificidade por Substrato , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVE: This article outlines a scalable system developed by the All of Us Research Program's Genetic Counseling Resource to vet a large database of healthcare resources for supporting participants with health-related DNA results. MATERIALS AND METHODS: After a literature review of established evaluation frameworks for health resources, we created SONAR, a 10-item framework and grading scale for health-related participant-facing resources. SONAR was used to review clinical resources that could be shared with participants during genetic counseling. RESULTS: Application of SONAR shortened resource approval time from 7 days to 1 day. About 256 resources were approved and 8 rejected through SONAR review. Most approved resources were relevant to participants nationwide (60.0%). The most common resource types were related to support groups (20%), cancer care (30.6%), and general educational resources (12.4%). All of Us genetic counselors provided 1161 approved resources during 3005 (38.6%) consults, mainly to local genetic counselors (29.9%), support groups (21.9%), and educational resources (21.0%). DISCUSSION: SONAR's systematic method simplifies resource vetting for healthcare providers, easing the burden of identifying and evaluating credible resources. Compiling these resources into a user-friendly database allows providers to share these resources efficiently, better equipping participants to complete follow up actions from health-related DNA results. CONCLUSION: The All of Us Genetic Counseling Resource connects participants receiving health-related DNA results with relevant follow-up resources on a high-volume, national level. This has been made possible by the creation of a novel resource database and validation system.
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The epithelial-to-mesenchymal transition (EMT) produces cancer cells that are invasive, migratory, and exhibit stem cell characteristics, hallmarks of cells that have the potential to generate metastases. Inducers of the EMT include several transcription factors (TFs), such as Goosecoid, Snail, and Twist, as well as the secreted TGF-beta1. Each of these factors is capable, on its own, of inducing an EMT in the human mammary epithelial (HMLE) cell line. However, the interactions between these regulators are poorly understood. Overexpression of each of the above EMT inducers up-regulates a subset of other EMT-inducing TFs, with Twist, Zeb1, Zeb2, TGF-beta1, and FOXC2 being commonly induced. Up-regulation of Slug and FOXC2 by either Snail or Twist does not depend on TGF-beta1 signaling. Gene expression signatures (GESs) derived by overexpressing EMT-inducing TFs reveal that the Twist GES and Snail GES are the most similar, although the Goosecoid GES is the least similar to the others. An EMT core signature was derived from the changes in gene expression shared by up-regulation of Gsc, Snail, Twist, and TGF-beta1 and by down-regulation of E-cadherin, loss of which can also trigger an EMT in certain cell types. The EMT core signature associates closely with the claudin-low and metaplastic breast cancer subtypes and correlates negatively with pathological complete response. Additionally, the expression level of FOXC1, another EMT inducer, correlates strongly with poor survival of breast cancer patients.
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Neoplasias da Mama/genética , Claudinas/genética , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Mesoderma/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Análise por Conglomerados , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteína Goosecoid/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta1/genética , Proteína 1 Relacionada a Twist/genéticaRESUMO
Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.
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Neoplasias Colorretais , Neoplasias Nasofaríngeas , Humanos , Arábia Saudita , Sequenciamento de Nucleotídeos em Larga Escala , Prevalência , Predisposição Genética para DoençaRESUMO
BACKGROUND: State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants-such as those related to familial hypercholesterolemia-as well as the cumulative impact of many common variants, as quantified by a polygenic score. OBJECTIVES: The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management. METHODS: Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure. RESULTS: There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging. CONCLUSIONS: Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.
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BACKGROUND: The All of Us Research Program (AoURP, "the program") is an initiative, sponsored by the National Institutes of Health (NIH), that aims to enroll one million people (or more) across the USA. Through repeated engagement of participants, a research resource is being created to enable a variety of future observational and interventional studies. The program has also committed to genomic data generation and returning important health-related information to participants. METHODS: Whole-genome sequencing (WGS), variant calling processes, data interpretation, and return-of-results procedures had to be created and receive an Investigational Device Exemption (IDE) from the United States Food and Drug Administration (FDA). The performance of the entire workflow was assessed through the largest known cross-center, WGS-based, validation activity that was refined iteratively through interactions with the FDA over many months. RESULTS: The accuracy and precision of the WGS process as a device for the return of certain health-related genomic results was determined to be sufficient, and an IDE was granted. CONCLUSIONS: We present here both the process of navigating the IDE application process with the FDA and the results of the validation study as a guide to future projects which may need to follow a similar path. Changes to the program in the future will be covered in supplementary submissions to the IDE and will support additional variant classes, sample types, and any expansion to the reportable regions.
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Farmacogenética , Saúde da População , Genômica , Humanos , Estados Unidos , Sequenciamento Completo do Genoma/métodosRESUMO
Excess liver fat, called hepatic steatosis, is a leading risk factor for end-stage liver disease and cardiometabolic diseases but often remains undiagnosed in clinical practice because of the need for direct imaging assessments. We developed an abdominal MRI-based machine-learning algorithm to accurately estimate liver fat (correlation coefficients, 0.97-0.99) from a truth dataset of 4,511 middle-aged UK Biobank participants, enabling quantification in 32,192 additional individuals. 17% of participants had predicted liver fat levels indicative of steatosis, and liver fat could not have been reliably estimated based on clinical factors such as BMI. A genome-wide association study of common genetic variants and liver fat replicated three known associations and identified five newly associated variants in or near the MTARC1, ADH1B, TRIB1, GPAM, and MAST3 genes (p < 3 × 10-8). A polygenic score integrating these eight genetic variants was strongly associated with future risk of chronic liver disease (hazard ratio > 1.32 per SD score, p < 9 × 10-17). Rare inactivating variants in the APOB or MTTP genes were identified in 0.8% of individuals with steatosis and conferred more than 6-fold risk (p < 2 × 10-5), highlighting a molecular subtype of hepatic steatosis characterized by defective secretion of apolipoprotein B-containing lipoproteins. We demonstrate that our imaging-based machine-learning model accurately estimates liver fat and may be useful in epidemiological and genetic studies of hepatic steatosis.
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Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/genética , Medição de Risco/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Participação do Paciente , Fatores de Risco , Inquéritos e Questionários , Telemedicina , Adulto JovemRESUMO
Publicly available genetic databases promote data sharing and fuel scientific discoveries for the prevention, treatment and management of disease. In 2018, we built Color Data, a user-friendly, open access database containing genotypic and self-reported phenotypic information from 50 000 individuals who were sequenced for 30 genes associated with hereditary cancer. In a continued effort to promote access to these types of data, we launched Color Data v2, an updated version of the Color Data database. This new release includes additional clinical genetic testing results from more than 18 000 individuals who were sequenced for 30 genes associated with hereditary cardiovascular conditions as well as polygenic risk scores for breast cancer, coronary artery disease and atrial fibrillation. In addition, we used self-reported phenotypic information to implement the following four clinical risk models: Gail Model for 5-year risk of breast cancer, Claus Model for lifetime risk of breast cancer, simple office-based Framingham Coronary Heart Disease Risk Score for 10-year risk of coronary heart disease and CHARGE-AF simple score for 5-year risk of atrial fibrillation. These new features and capabilities are highlighted through two sample queries in the database. We hope that the broad dissemination of these data will help researchers continue to explore genotype-phenotype correlations and identify novel variants for functional analysis, enabling scientific discoveries in the field of population genomics. Database URL: https://data.color.com/.
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Neoplasias da Mama , Predisposição Genética para Doença , Bases de Dados Factuais , Feminino , Estudos de Associação Genética , Genótipo , HumanosRESUMO
BACKGROUND: Barriers to genetic testing and subsequent family cascade screening for familial hypercholesterolemia (FH) include cost, patient and provider awareness, privacy and discrimination concerns, need for a physician order, underutilization of genetic counselors, and family concerns about the implications of genetic testing for care. OBJECTIVES: The objective of the study was to determine the uptake of genetic testing with cost and privacy removed. METHODS: The FH Foundation offered free genetic testing and counseling to patients in the patient portal of the CASCADE FH Registry, who had not previously undergone genetic testing for 3 genes associated with FH (LDLR, APOB, and PCSK9). The free testing offer was extended to first-degree relatives of participants who had a positive genetic test result for cascade screening. RESULTS: Of 435 eligible patients, 147 opted in to participate, 122 consented, and 110 (68.2% female, median age: 52 years) received genetic testing. Of the participants, 64 had a positive genetic test result for a pathogenic variant in LDLR (59) or APOB (5); 11 had a variant of uncertain significance. Only 3 first-degrees relatives underwent genetic testing. CONCLUSIONS: Although there was substantial interest in genetic testing, uptake of family cascade screening was poor. Innovative approaches to increase family cascade screening should be explored.
Assuntos
Testes Genéticos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Sistema de Registros , Adulto , Idoso , Confidencialidade , Custos e Análise de Custo , Feminino , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Sub-Saharan Africa (SSA) has a high proportion of premenopausal hormone receptor negative breast cancer. Previous studies reported a strikingly high prevalence of germline mutations in BRCA1 and BRCA2 among Nigerian patients with breast cancer. It is unknown if this exists in other SSA countries. METHODS: Breast cancer cases, unselected for age at diagnosis and family history, were recruited from tertiary hospitals in Kampala, Uganda and Yaoundé, Cameroon. Controls were women without breast cancer recruited from the same hospitals and age-matched to cases. A multigene sequencing panel was used to test for germline mutations. RESULTS: There were 196 cases and 185 controls with a mean age of 46.2 and 46.6 years for cases and controls, respectively. Among cases, 15.8% carried a pathogenic or likely pathogenic mutation in a breast cancer susceptibility gene: 5.6% in BRCA1, 5.6% in BRCA2, 1.5% in ATM, 1% in PALB2, 0.5% in BARD1, 0.5% in CDH1, and 0.5% in TP53. Among controls, 1.6% carried a mutation in one of these genes. Cases were 11-fold more likely to carry a mutation compared with controls (OR = 11.34; 95% confidence interval, 3.44-59.06; P < 0.001). The mean age of cases with BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations (P = 0.03). CONCLUSIONS: Our findings replicate the earlier report of a high proportion of mutations in BRCA1/2 among patients with symptomatic breast cancer in SSA. IMPACT: Given the high burden of inherited breast cancer in SSA countries, genetic risk assessment could be integrated into national cancer control plans.