RESUMEN
BACKGROUND: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. METHODS: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information. RESULTS: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options. CONCLUSION: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/).
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Proteína BRCA2/genética , Proteína BRCA1/genética , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Factores de Riesgo , Medición de Riesgo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Pruebas Genéticas , Paraganglioma/genética , Feocromocitoma/genética , Mutación de Línea Germinal/genética , Neoplasias de las Glándulas Suprarrenales/genética , Reino Unido , Predisposición Genética a la Enfermedad , Complejo II de Transporte de Electrones/genéticaRESUMEN
BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Diagnóstico Tardío , Predisposición Genética a la Enfermedad/epidemiología , Células Germinativas/patología , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/economía , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Ovariectomía , Medicina Estatal/economía , Salpingectomía , Reino Unido/epidemiología , Vigilancia de la Población , Análisis de Costo-EfectividadRESUMEN
INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
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Neoplasias de la Mama , Genes BRCA2 , Adulto , Femenino , Humanos , Índice de Masa Corporal , Proteína BRCA1/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína BRCA2/genética , Riesgo , Estudios Retrospectivos , Aumento de Peso/genética , Heterocigoto , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: The most common cancer diagnosed in germline TP53 pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers. OBJECTIVES: 1. To assess the frequency of germline TP53 PVs reported diagnostically in women with breast cancer at <30 years of age.2. To evaluate the impact of personal/family history and HER2 status on the likelihood of germline TP53 pathogenic/likely pathogenic variant (PV/LPV) identification. METHODS: Genetic test results from patients undergoing diagnostic germline TP53 tests between 2012 and 2017 in the four London Regional Clinical Genetics Services were reviewed. Clinical/pathology data and family history were extracted from genetics files for women diagnosed with breast cancer at <30 years. RESULTS: The overall germline TP53 PV/LPV variant detection rate was 9/270=3.3% in all women diagnosed with breast cancer at <30 years and 2/171=1.2% in those with no second/subsequent cancer diagnosis or family history of TP53-spectrum cancers. Breast cancers were significantly more likely to be HER2-positive in TP53 PV/LPV carriers than in non-carriers (p=0.00006). CONCLUSIONS: Germline TP53 PVs/LPVs are uncommon among women diagnosed with breast cancer aged <30 years without other relevant personal or family cancer history but have an important clinical impact when identified.
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Neoplasias de la Mama , Adulto , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Células Germinativas , Mutación de Línea Germinal/genética , Humanos , Londres/epidemiología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ÉÉ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ÉÉ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.
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Neoplasias de las Glándulas Suprarrenales , Succinato Deshidrogenasa , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Mutación de Línea Germinal , Humanos , Fenotipo , Succinato Deshidrogenasa/genética , VirulenciaRESUMEN
Rapid advances in sequencing technology have led to significant improvements in genomic analysis, resulting in increased understanding of the molecular basis of many endocrine conditions. Genomic testing for rare disease is being integrated into everyday clinical practice, as the importance of confirming a genetic diagnosis earlier in a patient's pathway helps direct their clinical care and specialized management. In England, the new nationally commissioned Genomic Medicine Service has started to deliver testing for rare and inherited disease and cancer somatic tissue via seven Genomic Laboratory Hubs. The range of genetic tests, technology employed and eligibility criteria for patient testing are all defined in the National Genomic Test Directory. This review provides practical guidance on how to access genomic testing for endocrine disease, how to interpret and relay results, and details how genetic counselling can help integrate results into ongoing care of the individual and their family. This article discusses general principles as well as specifics related to the process of genomic testing in England. We illustrate mainstream genetic testing with a clinical scenario involving an individual with inherited endocrine neoplasia, followed by a generic description of the different steps involved, including informed consent to proceed to diagnostic testing. Most genetic tests analyse multiple genes simultaneously by next-generation sequencing, and variant interpretation may yield not only pathogenic explanatory results, but also ambiguous outcomes, with variants of unknown significance or incidental findings. Delivery of results and posttest genetic counselling are therefore key components of integrating genetic testing into routine endocrine care.
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Enfermedades del Sistema Endocrino , Endocrinología , Enfermedades del Sistema Endocrino/diagnóstico , Enfermedades del Sistema Endocrino/genética , Endocrinología/métodos , Pruebas Genéticas/métodos , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , HumanosRESUMEN
OBJECTIVES: Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom. DESIGN AND PATIENTS: Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated. MEASUREMENTS: Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed. RESULTS: Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results. CONCLUSIONS: Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.
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Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/patología , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Paraganglioma/patología , Feocromocitoma/diagnóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
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Neoplasias de las Glándulas Suprarrenales , Carcinoma de Células Renales , Tumores del Estroma Gastrointestinal , Neoplasias Renales , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/genética , Femenino , Mutación de Línea Germinal/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Paraganglioma/genética , Paraganglioma/patología , Feocromocitoma/genética , Feocromocitoma/patología , Estudios Retrospectivos , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Reino UnidoRESUMEN
BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
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Reparación de la Incompatibilidad de ADN/genética , Detección Precoz del Cáncer , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor/sangre , Proteínas de Unión al ADN/genética , Mutación de Línea Germinal , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genéticaRESUMEN
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
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Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Neoplasias Primarias Múltiples/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Femenino , Pruebas Genéticas/métodos , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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Neoplasias de la Mama , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Mutación , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Anticonceptivos Orales/administración & dosificación , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Adulto , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
Constitutional pathogenic variants in TP53 are associated with Li-Fraumeni syndrome or the more recently described heritable TP53-related cancer syndrome and are associated with increased lifetime risks of a wide spectrum of cancers. Due to the broad tumour spectrum, surveillance for this patient group has been limited. To date, the only recommendation in the UK has been for annual breast MRI in women; however, more recently, a more intensive surveillance protocol including whole-body MRI (WB-MRI) has been recommended by International Expert Groups. To address the gap in surveillance for this patient group in the UK, the UK Cancer Genetics Group facilitated a 1-day consensus meeting to discuss a protocol for the UK. Using a preworkshop survey followed by structured discussion on the day, we achieved consensus for a UK surveillance protocol for TP53 carriers to be adopted by UK Clinical Genetics services. The key recommendations are for annual WB-MRI and dedicated brain MRI from birth, annual breast MRI from 20 years in women and three-four monthly abdominal ultrasound in children along with review in a dedicated clinic.
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Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.
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Pruebas Genéticas , Variación Genética/genética , Genómica , Neoplasias/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irlanda/epidemiología , Masculino , Neoplasias/epidemiología , Neoplasias/patología , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
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Síndrome de Li-Fraumeni/diagnóstico , Imagen por Resonancia Magnética , Neoplasias/diagnóstico , Proteína p53 Supresora de Tumor/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Heterocigoto , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagen , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patología , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/genética , Neoplasias/patología , Factores de Riesgo , Imagen de Cuerpo Entero , Adulto JovenRESUMEN
After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.
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BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Mutación , Salpingooforectomía/métodos , Adulto , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Estudios de Cohortes , Femenino , Humanos , Incidencia , Agencias Internacionales , Menopausia , Persona de Mediana Edad , Estudios Prospectivos , Conducta de Reducción del RiesgoRESUMEN
BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.
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Hipercalcemia , Hiperparatiroidismo Primario , Anciano , Niño , Femenino , Pruebas Genéticas , Humanos , Hipercalcemia/congénito , Hipercalcemia/genética , Hiperparatiroidismo Primario/genética , Recién Nacido , Estudios Retrospectivos , Reino UnidoRESUMEN
Pheochromocytoma (PC) and paraganglioma (PGL) are rare neuroendocrine tumors that occur throughout the body from the base of the skull to the pelvis. Sympathetic catecholamine-secreting tumors may be associated with hyperadrenergic symptoms and long-term morbidity if they are untreated. Typically biochemically silent, head and neck PGLs may result in cranial nerve palsies and symptoms due to localized mass effect. Tumors can arise sporadically or as part of an inheritable PC-PGL syndrome. Up to 40% of tumors are recognized to be associated with germline mutations in an increasing array of susceptibility genes, including those that appear to arise sporadically. Most commonly, up to 25% of all PC-PGLs are associated with mutations in one of the succinate dehydrogenase (SDH) enzyme subunit genes. The resulting familial PC-PGL syndrome varies according to the affected enzyme subunit (most commonly SDHB and SDHD mutations) with respect to tumor prevalence, location, age of onset, and risk of malignancy. Patients with SDH enzyme mutations have increased lifetime risk of developing multifocal tumors and malignancy. Early recognition of individuals at high risk, genetic testing, screening of family members, and lifelong surveillance programs are recommended, but not without health, economic, and psychologic implications. Anatomic and functional imaging is key to diagnosis, staging, treatment planning, and lifelong surveillance of these individuals. Radiologists must be aware of the imaging appearance of these varied tumors.©RSNA, 2019.