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1.
Genet Med ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568804

RESUMO

PURPOSE: ClinGen provides gene-specific guidance for interpretation of sequence variants in MYH7. We assessed laboratory and clinical impact of reclassification by the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) and ClinGen recommendations in 43 MYH7 variants reported by a diagnostic laboratory between 2013 and 2017. METHODS: Fifty-two proband reports containing MYH7 variants were reinterpreted by original ACMG-AMP and ClinGen guidelines. Evidence items were compared across schemes and reasons for classification differences recorded. Laboratory impact was assessed by number of recommended report reissues, and reclassifications coded as clinically "actionable" or "equivalent." Available pedigrees were reviewed to describe projected cascade impact. RESULTS: ClinGen produced a higher proportion of diagnostic classifications (65% of variants) compared with ACMG-AMP (54%) and fewer variants of uncertain significance (30% versus 42%). ClinGen classification resulted in actionable changes in 18% of variants with equal upgrades and downgrades from original report. ClinGen's revisions to PM1 and PS4 contributed to classification differences in 21% and 19% of variants respectively. Each classification change per proband report impacted, on average, 3.1 cascade reports with a further 6.3 first- and second-degree relatives potentially available for genotyping per family. CONCLUSION: ClinGen's gene-specific criteria provide expert-informed guidance for interpretation of MYH7 sequence variants. Periodic re-evaluation improves diagnostic confidence and should be considered by clinical and laboratory teams.

2.
J Genet Couns ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33470033

RESUMO

Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.

3.
J Neurol Sci ; 420: 117260, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33310205

RESUMO

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

4.
Hum Mutat ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300245

RESUMO

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), a cancer predisposition disorder inherited in an autosomal dominant pattern associated with high risk of malignancy, including early onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for twenty ACMG/AMP criteria while nine were deemed not applicable. The original strength level for ten criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data amongst experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification. This article is protected by copyright. All rights reserved.

5.
J Med Genet ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168572

RESUMO

BACKGROUND: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles. METHODS: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols. RESULTS: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information. CONCLUSION: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

6.
Psychooncology ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33006205

RESUMO

OBJECTIVE: Tamoxifen has been demonstrated to reduce breast cancer risk in high-risk, premenopausal women. Yet, very few young women with hereditary breast and ovarian cancer syndrome in Australia use tamoxifen, despite this being a less-invasive option compared to risk-reducing mastectomy. This study aims to examine young women's decision-making about and experience of taking tamoxifen to reduce their breast cancer risk. METHODS: Young women with a BRCA1/2 mutation participated in semi-structured qualitative interviews, recruited mainly from a metropolitan clinical genetics service. Data were analysed using an inductive, team-based approach to thematic analysis. RESULTS: Forty interviews with women aged 20-40 years with a BRCA1/2 mutation were conducted. Eleven women could not recall discussing tamoxifen with their healthcare provider or were too young to commence cancer risk management. Twenty-three women chose not to use tamoxifen because it is contraindicated for pregnancy or because it did not offer immediate and great enough risk reduction compared to bilateral risk-reducing mastectomy. Six women who were definite about not wanting to have children during the following 5-year period chose to use tamoxifen, and most experienced none or transient side effects. CONCLUSIONS: Decision-making about tamoxifen was nuanced and informed by considerations characteristic of young adulthood, especially childbearing. Therefore, clinical discussions about tamoxifen with young women with a BRCA1/2 mutation must include consideration of their reproductive plans.

8.
Cancer Genet ; 248-249: 11-17, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32966936

RESUMO

Pathogenic germline variants in the TP53 gene predispose to a wide range of cancers, known collectively as Li-Fraumeni syndrome (LFS). There has been much research aimed to identify genotype-phenotype correlations, that is, differences between variant location and/or effect and cancer spectrum. These correlations, should they exist, have potential to impact clinical management of carriers. Review of previously published studies showed a variety of study designs and inconsistency in reported findings. Here, we used pooled data from 427 TP53 carriers who had undergone multigene panel testing and 154 TP53 carriers identified by single-gene testing to investigate correlations between TP53 genotype (truncating variants, hotspot variants, other missense variants with dominant-negative effect, missense variants without dominant-negative effect) and a number of LFS-selected malignancies. Our results suggest that carriers of truncating and hotspot variants might be more likely to present with LFS cancers and have shorter time to first cancer diagnosis compared to carriers of other variant types. However, the differences observed were minor, and we conclude that there is currently insufficient evidence to consider location and/or molecular effect of pathogenic variants to assist with clinical management of TP53 carriers. Larger studies are necessary to confirm the correlations suggested by our analysis.

9.
Genet Med ; 22(11): 1883-1886, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32606442

RESUMO

PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

10.
JAMA Oncol ; 6(8): 1218-1230, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32614418

RESUMO

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

11.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
12.
Hum Mutat ; 41(9): 1555-1562, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32485079

RESUMO

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.

13.
Nat Commun ; 11(1): 1640, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242007

RESUMO

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.


Assuntos
Cistadenocarcinoma Seroso/genética , Exoma , Heterogeneidade Genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Mutação com Perda de Função , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Breast Cancer Res ; 22(1): 21, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066492

RESUMO

Polygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discussed.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Feminino , Testes Genéticos/métodos , Humanos , Fatores de Risco
15.
Nat Commun ; 11(1): 435, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974348

RESUMO

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.


Assuntos
Bases de Dados Genéticas , Variação Genética , Genoma Humano , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Neoplasias/genética , Desempenho Físico Funcional , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
16.
Genet Med ; 22(5): 831-839, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31996782

RESUMO

PURPOSE: Women who inherit a BRCA1 or BRCA2 pathogenic variant are at high risk of developing breast and ovarian cancer. Evidence for the effectiveness and cost-effectiveness of long-term management in clinical practice is lacking. The purpose of this study was to evaluate the real-world cost-effectiveness of BRCA carrier management within a structured clinical program. METHODS: Lifetime health outcomes and costs of clinical management for female unaffected BRCA carriers aged 20 were measured using a microsimulation model. For the intervention, women could attend a high-risk clinic, undergo risk-reducing surgery, and receive annual breast screening. Input data for the model was from a clinical database of 983 BRCA carriers. The comparator was no risk management. Outcomes were discounted at 5%. RESULTS: The incremental cost-effectiveness ratio for the program was $32,359 to $48,263 per quality-adjusted life-year (QALY). Limiting uptake of risk-reducing salpingo-oophorectomy to <50% of carriers decreased cost-effectiveness by $7000-8000 per QALY. Achieving perfect adherence to guidelines was less cost-effective for BRCA2 due to increased risk-reducing mastectomy costs with smaller incremental health benefit. CONCLUSION: Long-term management of BRCA carriers within a structured clinical program is cost-effective. Suboptimal adherence to risk management guidelines can substantially affect outcomes and is an important consideration for future studies.

17.
Hum Mutat ; 41(3): 537-542, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898864

RESUMO

The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant classification are widely used for clinical interpretation of gene test results. These guidelines may be specified to genes/syndromes of interest to improve their utility in the clinical setting. As part of these specifications, phenotype-related criteria can be detailed and weighted depending on the personal history of disease for a given variant carrier. We investigated how ascertainment can affect the significance and/or weight of patient phenotype as a predictor of germline-variant pathogenicity, using the Li-Fraumeni Syndrome gene TP53 as an example. Likelihood ratios in favor of variant pathogenicity were determined for a report of the personal history of several TP53-related cancers, using data from 2,656 probands undergoing single-gene testing (SGT) and 15,483 undergoing multi-gene panel testing (MGPT). Overall, TP53-associated cancers were more predictive of pathogenicity, and demonstrated greater evidence weight, in the MGPT versus SGT dataset. This observation is almost certainly explained by differences in proband ascertainment for the two streams of testing, and these findings have implications for germline-variant classification using ACMG/AMP guidelines.

18.
Clin Genet ; 97(3): 492-501, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833054

RESUMO

Polygenic risk scores (PRSs) are increasingly being implemented to assess breast cancer risk. This study aimed to assess and determine factors associated with uptake of PRS among women at increased risk of breast cancer for whom genetic testing to date had been uninformative. Participants were recruited from the Variants in Practice study from which breast cancer PRS had been calculated. Four hundred women were notified by letter of the availability of their PRS and invited to complete a self-administered survey comprising several validated scales. Considering non-participants, uptake of PRS was between 61.8% and 42.1%. Multivariate logistic regression identified that women were more likely to receive their PRS if they reported greater benefits (odds ratio [OR] = 1.17, P = .011) and fewer barriers to receiving their PRS (OR = 0.80, P = .007), had completed higher level education (OR = 3.32, P = .004), and did not have daughters (0.29, P = .006). Uptake of breast cancer PRS varied according to several testing- and patient-related factors. Knowledge of these factors will facilitate the implementation of polygenic testing in clinical practice and support informed decision making by patients.

19.
Alzheimers Dement ; 15(12): 1612-1623, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31506248

RESUMO

INTRODUCTION: Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These "resilient" individuals may carry protective genetic factors. METHODS: This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. RESULTS: Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. DISCUSSION: We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.


Assuntos
Doença de Alzheimer , Apolipoproteína E4/genética , Homozigoto , Fatores de Proteção , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
Value Health ; 22(8): 854-862, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31426925

RESUMO

OBJECTIVES: To develop a validated model for evaluating the real-world effectiveness of long-term clinical management strategies for women with germline BRCA1 or BRCA2 pathogenic variants. METHODS: A microsimulation model was developed that included a BRCA-specific natural history for breast and ovarian cancer, a clinical framework for carrier follow-up, and cancer risk management strategies (breast screening, risk-reducing mastectomy, and bilateral salpingo-oophorectomy). Adherence rates and outcomes for breast screening and risk-reducing surgery were obtained from BRCA carriers seen through a familial cancer service in Melbourne, Australia. The model was assessed for internal and external validity. The model was used to compare women perfectly adhering to screening recommendations versus actual adherence of the clinical cohort. RESULTS: The model accurately predicted cancer incidence, pathology, and mortality. Using actual adherence for breast screening resulted in additional breast cancer deaths (per 1000 women: BRCA1, 2.7; BRCA2, 1.6) compared with perfect screening adherence. This decreased average life expectancy by 0.30 life-years for BRCA1 and 0.07 life-years for BRCA2. When carriers had access to risk-reducing mastectomy, the benefit from improved screening adherence was not significant. CONCLUSIONS: The developed model is a good descriptor of BRCA carriers' lifetime trajectory and its modification by use of risk management strategies alone or in combination. Evaluations of breast screening in BRCA carriers may overestimate the benefits of screening programs unless adherence is considered. By incorporating real-world clinical practice and patient behavior, this model can assist in developing clinical services and improving clinical outcomes for carriers.


Assuntos
Proteína BRCA1/biossíntese , Proteína BRCA2/biossíntese , Neoplasias da Mama/epidemiologia , Técnicas de Apoio para a Decisão , Neoplasias Ovarianas/epidemiologia , Adulto , Fatores Etários , Austrália , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Gestão de Riscos , Salpingo-Ooforectomia/estatística & dados numéricos
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