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BACKGROUND: Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. METHODS: Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. DISCUSSION: This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1.
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Pruebas Genéticas , Genómica , Humanos , Pruebas Genéticas/métodos , Genómica/métodos , Registros Electrónicos de Salud , Economía del Comportamiento , Ciencia de la ImplementaciónRESUMEN
Research participants report interest in receiving genetic research results. How best to return results remains unclear. In this randomized pilot study, we sought to assess the feasibility of returning actionable research results through a two-step process including a patient-centered digital intervention as compared to a genetic counselor (GC) in the Penn Medicine biobank. In Step 1, participants with an actionable result and procedural controls (no actionable result) were invited to digital pre-disclosure education and provided options for opting out of results. In Step 2, those with actionable results who had not opted out were randomized to receive results via a digital disclosure intervention or with a GC. Five participants (2%) opted out of results after Step 1. After both steps, 52/113 (46.0%) of eligible cases received results, 5 (4.4%) actively declined results, 34 (30.1%) passively declined and 22 (19.5%) could not be reached. Receiving results was associated with younger age (p<0.001), completing pre-disclosure education (p<0.001) and being in the GC arm (p=0.06). Being older, female, and of Black race were associated with being unable to reach. Older age and Black race were associated with passively declining. 47% of those who received results did not have personal or family history to suggest the mutation, and 55.1% completed clinical confirmation testing. The use of digital tools may be acceptable to participants and could reduce costs of returning results. Low uptake, disparities in uptake, and barriers to confirmation testing will be important to address to realize the benefit of returning actionable research results.
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PURPOSE: Germline genetic testing (GT) is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC), but the traditional clinical genetics infrastructure is limited in addressing the unique needs of this population. We describe the integration of point of care (POC) GT into routine clinical practice for all patients with PDAC at an academic medical center. METHODS: We developed a clinical POC workflow that leverages electronic health record (EHR) tools and behavioral nudges to enhance the sustainability and scalability of our previously described research-based POC model. For each of the research and clinical POC cohorts, we calculated the percentage of eligible patients who underwent GT. We used Wilcoxon rank-sum and Pearson's chi-squared tests to compare patients who did and did not undergo GT. We conducted surveys among oncology clinicians to evaluate the acceptability, appropriateness, and feasibility of the clinical POC model. RESULTS: The research POC cohort included 905 patients, of whom 694 (76.7%) underwent GT. The clinical POC cohort included 148 patients, of whom 126 (85.1%) underwent GT. Patients who underwent GT in the research POC cohort were significantly younger (median age, 67.0 v 70.9 years; P = .031) and more likely to be White (82.1% v 68.7%; P < .001) and commercially insured (41.8% v 28.0%; P < .001) compared with those who did not; there were no significant differences between GT groups in the clinical POC cohort. Oncology clinicians found the clinical POC model to be acceptable (mean 4.4/5), appropriate (4.6/5), feasible (4.0/5), and have a positive impact on their patients (4.9/5). CONCLUSION: A clinical POC model leveraging EHR tools and behavioral nudges is acceptable, appropriate, feasible, and associated with a >85% GT rate among patients with PDAC.
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Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Estudios de Casos y Controles , Factores de RiesgoRESUMEN
African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Transcriptoma , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Población Negra/genética , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Negro o Afroamericano , Estados UnidosRESUMEN
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.
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Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Estudio de Asociación del Genoma Completo/métodos , Neoplasias de la Mama/genética , Población Negra/genética , Estudios de Casos y Controles , Factores de Riesgo , Neoplasias de la Mama Triple Negativas/genética , Alelos , Herencia Multifactorial/genética , Persona de Mediana Edad , Sitios Genéticos , Población Blanca/genéticaRESUMEN
Deep learning models for variant pathogenicity prediction can recapitulate expert-curated annotations, but their performance remains unexplored on actual disease phenotypes in a real-world setting. Here, we apply three state-of-the-art pathogenicity prediction models to classify hereditary breast cancer gene variants in the UK Biobank. Predicted pathogenic variants in BRCA1, BRCA2 and PALB2, but not ATM and CHEK2, were associated with increased breast cancer risk. We explored gene-specific score thresholds for variant pathogenicity, finding that they could improve model performance. However, when specifically tasked with classifying variants of uncertain significance, the deep learning models were generally of limited clinical utility.
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BACKGROUND: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. PATIENTS AND METHODS: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. RESULTS: Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. CONCLUSIONS: Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.
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Pruebas Genéticas , Mutación de Línea Germinal , Síndrome de Li-Fraumeni , Mosaicismo , Proteína p53 Supresora de Tumor , Humanos , Pruebas Genéticas/métodos , Proteína p53 Supresora de Tumor/genética , Femenino , Masculino , Síndrome de Li-Fraumeni/genética , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.
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Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Femenino , Humanos , Población Negra/genética , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes.
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Melanoma , Neoplasias Cutáneas , Animales , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Modelos Animales de Enfermedad , Ciclo Celular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk. OBJECTIVE: To identify coding genomic variants associated with predisposition to TGCT. DESIGN, SETTING, AND PARTICIPANTS: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk. RESULTS AND LIMITATIONS: Gene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 × 10-11), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10-10), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10-4). CONCLUSIONS: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with co-translational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment. PATIENT SUMMARY: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer.
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Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Secuenciación del Exoma , Estudios de Casos y Controles , Neoplasias de Células Germinales y Embrionarias/genética , Células Germinativas/patologíaRESUMEN
BACKGROUND: Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes. RESULTS: Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1. CONCLUSIONS: Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patología , Histonas/genética , Histonas/metabolismo , Metilación de ADN , Paraganglioma/genética , Paraganglioma/patología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Germline genetic testing is recommended by the National Comprehensive Cancer Network (NCCN) for individuals including, but not limited to, those with a personal history of ovarian cancer, young-onset (< 50 years) breast cancer, and a family history of ovarian cancer or male breast cancer. Genetic testing is underused overall, and rates are consistently lower among Black and Hispanic populations. Behavioral economics-informed implementation strategies, or nudges, directed towards patients and clinicians may increase the use of this evidence-based clinical practice. METHODS: Patients meeting eligibility for germline genetic testing for breast and ovarian cancer will be identified using electronic phenotyping algorithms. A pragmatic cohort study will test three sequential strategies to promote genetic testing, two directed at patients and one directed at clinicians, deployed in the electronic health record (EHR) for patients in OB-GYN clinics across a diverse academic medical center. We will use rapid cycle approaches informed by relevant clinician and patient experiences, health equity, and behavioral economics to optimize and de-risk our strategies and methods before trial initiation. Step 1 will send patients messages through the health system patient portal. For non-responders, step 2 will reach out to patients via text message. For non-responders, Step 3 will contact patients' clinicians using a novel "pend and send" tool in the EHR. The primary implementation outcome is engagement with germline genetic testing for breast and ovarian cancer predisposition, defined as a scheduled genetic counseling appointment. Patient data collected through the EHR (e.g., race/ethnicity, geocoded address) will be examined as moderators of the impact of the strategies. DISCUSSION: This study will be one of the first to sequentially examine the effects of patient- and clinician-directed strategies informed by behavioral economics on engagement with breast and ovarian cancer genetic testing. The pragmatic and sequential design will facilitate a large and diverse patient sample, allow for the assessment of incremental gains from different implementation strategies, and permit the assessment of moderators of strategy effectiveness. The findings may help determine the impact of low-cost, highly transportable implementation strategies that can be integrated into healthcare systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05721326. Registered February 10, 2023. https://www. CLINICALTRIALS: gov/study/NCT05721326.
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Ginecología , Neoplasias Ováricas , Femenino , Humanos , Masculino , Estudios de Cohortes , Registros Electrónicos de Salud , Pruebas Genéticas/métodos , Ensayos Clínicos Pragmáticos como Asunto , AdultoRESUMEN
ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.
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Loss of function variants in the NF1 gene cause neurofibromatosis type 1 (NF1), a genetic disorder characterized by complete penetrance, prevalence of 1 in 3,000, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is entirely based on patients ascertained through phenotype-first approaches. Leveraging a genotype-first approach in two large patient cohorts, we demonstrate unexpectedly high prevalence (1 in 450-750) of NF1 pathogenic variants. Half were identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants were not associated with classic NF1 features but were associated with an increased incidence of malignancy compared to a control population. Our findings suggest that NF1 pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.
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PURPOSE: We developed a web-based education intervention as an alternative to predisclosure education with a genetic counselor (GC) to reduce participant burden and provider costs with return of genetic research results. METHODS: Women at three sites who participated in 11 gene discovery research studies were contacted to consider receiving cancer genetic research results. Participants could complete predisclosure education through web education or with a GC. Outcomes included uptake of research results, factors associated with uptake, and patient-reported outcomes. RESULTS: Of 819 participants, 178 actively (21.7%) and 167 passively (20.4%) declined return of results; 474 (57.9%) were enrolled. Most (60.3%) received results although this was lower than the 70% uptake we hypothesized. Passive and active decliners were more likely to be Black, to have less education, and to have not received phone follow-up after the invitation letter. Most participants selected web education (88.5%) as an alternative to speaking with a GC, but some did not complete or receive results. Knowledge increased significantly from baseline to other time points with no significant differences between those who received web versus GC education. There were no significant increases in distress between web and GC education. CONCLUSION: Interest in web-based predisclosure education for return of genetic research results was high although it did not increase uptake of results. We found no negative patient-reported outcomes with web education, suggesting that it is a viable alternative delivery model for reducing burdens and costs of returning genetic research results. Attention to attrition and lower uptake of results among Black participants and those with less formal education are important areas for future research.
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Medición de Resultados Informados por el Paciente , Teléfono , Humanos , Femenino , Escolaridad , Investigación Genética , InternetRESUMEN
PURPOSE: Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS: A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS: Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% (P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION: A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.
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Proteína BRCA1 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Recombinación Homóloga/genéticaRESUMEN
PURPOSE: To develop an electronic health record (EHR)-based clinical decision support (CDS) tool to promote guideline-recommended cancer risk management among patients with Lynch syndrome (LS), an inherited cancer syndrome that confers an increased risk of colorectal and other cancer types. MATERIALS AND METHODS: We conducted a cross-sectional study to determine the baseline prevalence and predictors of guideline-recommended colonic surveillance and annual genetics program visits among patients with LS. Multivariable log-binomial regressions estimated prevalence ratios (PRs) of cancer risk management adherence by baseline sociodemographic and clinical characteristics. These analyses provided rationale for the development of an EHR-based CDS tool to support patients and clinicians with LS-related endoscopic surveillance and annual genetics program visits. The CDS leverages an EHR platform linking discrete genetic data to LS Genomic Indicators, in turn driving downstream clinician- and patient-facing CDS. RESULTS: Among 323 patients with LS, cross-sectional adherence to colonic surveillance and annual genetics program visits was 69.3% and 55.4%, respectively. Patients with recent electronic patient portal use were more likely to be adherent to colonic surveillance (PR, 1.67; 95% CI, 1.11 to 2.52). Patients more recently diagnosed with LS were more likely to be adherent to annual genetics program visits (PR, 0.58; 95% CI, 0.44 to 0.76 for 2-4 years; PR, 0.62; 95% CI, 0.51 to 0.75 for ≥4 compared with <2 years). Our EHR-based CDS tool is now active for 421 patients with LS throughout our health system. CONCLUSION: We have successfully developed an EHR-based CDS tool to promote guideline-recommended cancer risk management among patients with LS.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Sistemas de Apoyo a Decisiones Clínicas , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Estudios Transversales , Registros Electrónicos de Salud , ElectrónicaRESUMEN
Background: The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype. Methods: Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas. Cases were filtered for variants (disease-associated or of uncertain significance) in 14 HR pathway genes, including BRCA1, BRCA2, and ATM. The clinical, pathological and molecular data were reviewed. Results: Sixty-one HR pathway gene variants in 56 patients with primary lung cancer were identified. Further filtering by variant allele fraction (VAF) of ≥30% identified 17 HR pathway gene variants in 17 patients. ATM gene variants were most the commonly identified (9/17), including two patients with c.7271T>G (p.V2424G), a variant in the germline that is associated with increased familial cancer risk. Four (4/17) patients had a family history of lung cancer, among which three patients had ATM gene variants suspected to be germline in origin. In three other patients with BRCA1/2 or PALB2 gene variants who had undergone germline testing, the variants were confirmed to be germline; lung cancer was the sentinel cancer in two of these patients with a BRCA1 or PALB2 variant. Conclusions: Genomic variants in the HR repair pathway identified in tumor-only sequencing and occurring at higher VAFs (i.e., ≥30%) may suggest a germline origin. Correlating with personal and family history, a subset of these variants is also suggested to be associated with familial cancer risks. Patient age, smoking history and driver mutation status are expected to be a poor screening tool in identifying these patients. Finally, the relative enrichment for ATM variants in our cohort suggests a possible association between ATM mutation and lung cancer risk.