RESUMEN
BACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.
Asunto(s)
Laboratorios , Neoplasias , Humanos , Flujo de Trabajo , Medicina Estatal , Genómica , Reino UnidoRESUMEN
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.
Asunto(s)
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
OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
Asunto(s)
Neoplasias , Medicina Estatal , Humanos , Reparación de la Incompatibilidad de ADN/genética , Laboratorios , GenómicaRESUMEN
Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).
Asunto(s)
Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Médula Ósea , Medicina Estatal , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Genómica , Factores de Transcripción/genética , Reino UnidoRESUMEN
The implementation of whole genome sequencing and large somatic gene panels in haematological malignancies is identifying an increasing number of individuals with either potential or confirmed germline predisposition to haematological malignancy. There are currently no national or international best practice guidelines with respect to management of carriers of such variants or of their at-risk relatives. To address this gap, the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group held a workshop over two days on 28-29th April 2022, with the aim of establishing consensus guidelines on relevant clinical and laboratory pathways. The workshop focussed on the management of disease-causing germline variation in the following genes: DDX41, CEBPA, RUNX1, ANKRD26, ETV6, GATA2. Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in several areas. In particular, high consensus was achieved on issues regarding standardised reporting, variant classification, multidisciplinary team working and patient support. The best practice recommendations from this meeting may be applicable to an expanding number of other genes in this setting.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Hematológicas , Humanos , Medicina Estatal , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Mutación de Línea Germinal , Inglaterra , Células GerminativasRESUMEN
Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.
Asunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Síndromes Neoplásicos Hereditarios , Adolescente , Antineoplásicos/efectos adversos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Humanos , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Gestión de RiesgosRESUMEN
Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer. Individuals with identified pathogenic variants in the BRCA1 or BRCA2 gene can benefit from cancer risk-reducing strategies. In the recent years, there has been an increase in the demand of genetic services. In light of the ongoing COVID19 pandemic, alternatives to face-to-face consultations have had to be considered and adopted, including telemedicine. Informed consent is necessary for genetic testing. Studies have suggested that increased levels of cancer-specific distress may impair the patient's ability to retain information, therefore, providing informed consent. This systematic review and meta-analysis aimed to answer if telephone genetic counseling for BRCA1 and BRCA2 genetic testing is non-inferior to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Databases of Medline, Embase, PsycINFO, CINAHL, SciELO, Web of Science, CENTRAL, ProQuest Dissertation & Theses Database, Clinicaltrials.gov, EU clinical trials register were accessed to identify any published or unpublished relevant literature. Random-effects models were used for the meta-analysis. Four studies were included in the qualitative synthesis of the results. Three studies were included in the quantitative synthesis of the results. Telephone genetic counseling was non-inferior compared to in-person genetic counseling for the outcomes of cancer-specific distress and genetic knowledge. Sensitivity analysis corroborated the main results. Telephone genetic counseling for BRCA1/BRCA2 genetic testing may be an alternative model of delivering genetic services in front of the increased demand/or when required by social context. However, the paucity of the evidence prevents from drawing strong conclusions regarding the generalizability of these results. Further research is needed to strengthen the conclusions.
Asunto(s)
Neoplasias de la Mama , COVID-19 , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Femenino , Genes BRCA1 , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Mutación , Neoplasias Ováricas/genética , SARS-CoV-2 , TeléfonoRESUMEN
Down syndrome (DS) is associated with a complex respiratory phenotype, including obstructive sleep apnea syndrome (OSAS). The study explored parent-reported prevalence and presentation of OSAS symptoms in children and adolescents with DS in Ireland. It also investigated treatment and compliance in those who have OSAS. A cross-sectional survey was distributed to parents registered with Down Syndrome Ireland (DSI) (n = 1,343). Data was collated and analyzed using SPSS v23. The response rate was 393 (29%). Twenty-one percent of parents (n = 84) reported a diagnosis of OSAS in their child. The parents of children reported as compliant with continuous positive airway pressure (CPAP) were more likely to report a perceived benefit of treatment (p = .018). Ninety-two percent (n = 212) of children without a formal diagnosis of OSAS had at least one symptom (median 4 symptoms) of the condition. This, the largest survey of parental reporting of OSAS or its symptoms, demonstrates a high reported prevalence of symptoms in children and adolescents with DS in Ireland without a formal diagnosis of OSAS, indicating under-recognition. In treated patients, perception of the benefit of CPAP correlated with reported compliance, suggesting a need for tailored education.
Asunto(s)
Síndrome de Down/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Irlanda/epidemiología , Masculino , Pronóstico , Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño/etiología , Apnea Obstructiva del Sueño/patología , Encuestas y CuestionariosRESUMEN
Congenital anomalies of the upper limbs are rare and etiologically heterogeneous. Herein, we report a male infant with non-syndromic bilateral Type Vb ulnar longitudinal dysplasia with radiohumeral synostosis (apparent humeral bifurcation), and bilateral oligo-ectro-syndactyly who was born following an uncomplicated pregnancy, with no maternal use of prescription or illicit medication. Array CGH (60,000 probes) and chromosomal breakage analysis (DEB) were normal. Similar appearances have been reported in children exposed to thalidomide or cocaine, but sporadic patients have also been reported without a prior history of exposure to known teratogens.
Asunto(s)
Fenotipo , Deformidades Congénitas de las Extremidades Superiores/diagnóstico , Rotura Cromosómica , Hibridación Genómica Comparativa , Humanos , Lactante , Masculino , RadiografíaRESUMEN
BACKGROUND: Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. AIMS: We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. RESULTS: Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. CONCLUSION: Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.
Asunto(s)
Pruebas Genéticas , Humanos , Femenino , Masculino , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Adulto , Adolescente , Niño , Lactante , Preescolar , Persona de Mediana Edad , Irlanda , Adulto Joven , Recién Nacido , Miosinas Cardíacas/genética , Anciano , Cardiomiopatías/genética , Cardiomiopatías/diagnósticoRESUMEN
BACKGROUND: A consistent finding in health care is that interns (junior physicians) are unwilling to "speak up" to attendings or consultants (senior physicians), which involves the related behaviors of challenging or questioning the actions of attendings, seeking guidance about one's own performance, and reporting one's errors. Training designed to encourage interns to speak up was designed, conducted, and evaluated at University Hospital Galway, an academic teaching hospital affiliated with the National University of Ireland, Galway, in January 2012-March 2012 and November 2012-January 2013. METHOD: Training, which was based on the Crew Resource Management model, was constructed around filmed stories of attending physicians describing situations in which, when they were interns, their communication and assertiveness skills were challenged, and their reflections on what they could have done better. RESULTS: A total of 110 interns attended the training. The feedback from participants was positive. There was a significant increase in knowledge as a result of the training, and some evidence to support a shift in attitudes in the desirable direction relating to the need to speak up to seniors. No effect of the training was found on behavior. CONCLUSIONS: The willingness to share examples of poor performance is an important part of building a good safety culture. Listening to the stories ofattendings describing and reflecting on a situation in which they struggled is a powerful teaching method for training interns in the communication and assertiveness skills that are critical to their job. However, a sustained change in attitudes and behavior to speaking up will require a reinforcement of learning with deliberate practice to develop the skills introduced through the training program.
Asunto(s)
Comunicación , Capacitación en Servicio/organización & administración , Internado y Residencia/organización & administración , Actitud del Personal de Salud , Revelación , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: The National Screening Program for colorectal cancer is scheduled to commence in the near future. Previous studies on the topic of colorectal cancer and screening have highlighted paucity in public awareness of epidemiology, symptoms and signs of colorectal cancer. The aim of this study was to assess understanding of colorectal cancer and screening in a representative sample of the local catchment population of Mayo General Hospital. METHODS: A prospective cohort study was instituted utilising an anonymous survey, which was distributed at consecutive general surgical out-patient clinics over a one month period prior to initiation of the screening program. Data collected included demographics, presenting complaint type and duration, and general knowledge of colorectal cancer facts. Attitudes towards screening were also evaluated. RESULTS: Eighty-eight of the one hundred and thirty six patients sampled were female (65%). Thirty-six per cent of the sample was within the screening target age-group (55-74), with mean age 53 years (+/-18). Most respondents recognised bleeding per rectum as a possible symptom of colorectal cancer. A significant proportion, however, incorrectly selected less sinister symptoms as concerning, while only fifty per cent correctly cited weight loss. Family history was acknowledged as a risk factor by fifty-seven per cent with age and gender cited less often (29%, 4%), while forty-seven per cent incorrectly cited stress as a risk. Screening was defined as testing of symptomatic patients or those with a positive family history by eighty-one per cent of respondents, with only nineteen per cent associating screening with an asymptomatic cohort. Strikingly, twenty-five per cent of patients would decline screening. CONCLUSIONS: There remains poverty of awareness regarding colorectal cancer. More public health initiatives are required to help improve understanding of the disease process, and to improve public compliance with the screening initiative.
Asunto(s)
Colonoscopía/psicología , Neoplasias Colorrectales/psicología , Detección Precoz del Cáncer/psicología , Conocimientos, Actitudes y Práctica en Salud , Tamizaje Masivo/psicología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Femenino , Encuestas de Atención de la Salud , Humanos , Irlanda/epidemiología , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud , Estudios Prospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.
Asunto(s)
Carcinoma Basocelular , Síndrome de Muir-Torre , Neoplasias de las Glándulas Sebáceas , Humanos , Síndrome de Muir-Torre/genética , Inestabilidad de Microsatélites , Neoplasias de las Glándulas Sebáceas/genética , Genotipo , Proteína 2 Homóloga a MutS/genéticaRESUMEN
Background: Germline mutations in the ataxia telangiectasia mutated (ATM) gene occur in 0.5-1% of the overall population and are associated with tumour predisposition. The clinical and pathological features of ATM-mutated prostate cancer (PC) are poorly defined but have been associated with lethal PC. Objective: To report on the clinical characteristics including family history and clinical outcomes of a cohort of patients with advanced metastatic castration-resistant PC (CRPC) who were found to have germline ATM mutations after mutation detection by initial tumour DNA sequencing. Design setting and participants: We acquired germline ATM mutation data by saliva next-generation sequencing from patients with ATM mutations in PC biopsies sequenced between January 2014 and January 2022. Demographics, family history, and clinical data were collected retrospectively. Outcome measurements and statistical analysis: Outcome endpoints were based on overall survival (OS) and time from diagnosis to CRPC. Data were analysed using R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). Results and limitations: Overall, seven patients (n = 7/1217; 0.6%) had germline ATM mutations detected, with five of them having a family history of malignancies, including breast, prostate, pancreas, and gastric cancer; leukaemia; and lymphoma. Two patients had concomitant somatic mutations in tumour biopsies in genes other than ATM, while two patients were found to carry more than one ATM pathogenic mutation. Five tumours in germline ATM variant carriers had loss of ATM by immunohistochemistry. The median OS from diagnosis was 7.1 yr (range 2.9-14 yr) and the median OS from CRPC was 5.3 yr (range 2.2-7.3 yr). When comparing these data with PC patients sequenced by The Cancer Genome Atlas, we found that the spatial localisation of mutations was similar, with distribution of alterations occurring on similar positions in the ATM gene. Interestingly, these include a mutation within the FRAP-ATM-TRRAP (FAT) domain, suggesting that this represents a mutational hotspot for ATM. Conclusions: Germline ATM mutations are rare in patients with lethal PC but occur at mutational hotspots; further research is warranted to better characterise the family histories of these men and PC clinical course. Patient summary: In this report, we studied the clinical and pathological features of advanced prostate cancers associated with germline mutations in the ATM gene. We found that most patients had a strong family history of cancer and that this mutation might predict the course of these prostate cancers, as well as response to specific treatments.
RESUMEN
PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.
Asunto(s)
Neoplasias de la Mama , Fibroadenoma , Fibroma , Síndrome de Hamartoma Múltiple , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Fibroadenoma/genética , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/genética , Humanos , Fosfohidrolasa PTEN/genética , Vulva/patologíaRESUMEN
FH Tumour Predisposition Syndrome, also known as Hereditary Leiomyomatosis and renal cell cancer (HLRCC), or Reed Syndrome, is an autosomal dominant condition clinically characterized by multiple cutaneous leiomyomas, multiple early-onset uterine leiomyomas and early-onset renal cell cancer. Here we report a young female with FH Tumour Predisposition Syndrome with no clinical features except early-onset uterine leiomyomas. Whilst there is a significant history of uterine leiomyomas in her family, there is no history of cutaneous leiomyomas or renal cell cancer (RCC). Uterine leiomyomatosis in young adults may represent a narrow phenotypic variant of FH Tumour Predisposition Syndrome. It is important that young women who present with multiple leiomyomata or leiomyomata with atypical features are referred for molecular genetic testing.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Adolescente , Carcinoma de Células Renales/genética , Femenino , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Renales/genética , Leiomiomatosis/genética , Leiomiomatosis/patología , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto JovenRESUMEN
BACKGROUND: As genomic profiling of constitutional and tumour-derived DNA becomes increasingly critical in cancer risk estimation, prognostication and treatment, there is a growing need for clinicians involved in cancer care to up-skill in Cancer Genetics. In the Republic of Ireland (ROI), this is particularly crucial, given a paucity of vocationally trained Clinical Geneticists per capita compared to other European countries. AIMS: We aimed to assess the self-reported confidence of postgraduate medical/surgical trainees in ROI in requesting, interpreting, and managing genomic data in patients with cancer, and to assess their selfreported experience, and demand for future training in this area. METHODS: A cross-sectional survey of postgraduate trainees in four specialties (Medical and Radiation Oncology, Surgery, and Obstetrics and Gynaecology (O&G)), training in ROI, was undertaken. A bespoke electronic questionnaire was designed to capture data regarding preceding experience, and confidence across several hypothetical clinical scenarios involving genomic testing. The survey was circulated to eligible participants by training programme administrators, after relevant institutional ethical approval. Data was collected anonymously. RESULTS: The study cohort included 62 respondents. A paucity of cancer genetics training at every level was demonstrated, with "hardly any" or "none at all" reported by 47(76%), 62(100%), and 50(81%) during undergraduate, core specialty, and higher specialist training, respectively. A relative lack of confidence in all clinical scenarios was apparent, particularly among Surgery/O&G trainees. Most respondents would value more training in Cancer Genetics. CONCLUSIONS: This study demonstrates an unmet need in dedicated Cancer Genetics training for postgraduate specialty trainees in ROI.
Asunto(s)
Medicina , Neoplasias , Estudios Transversales , Educación de Postgrado en Medicina , Femenino , Humanos , Irlanda , Embarazo , Encuestas y CuestionariosRESUMEN
INTRODUCTION: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic. METHODS: A pilot study assessing Guardant360™ cfDNA-NGS in patients with radiological-suspected advanced-stage lung cancer was performed at an academic cancer centre during COVID-19. Variants were tiered using AMP/ASCO/CAP guidelines and discussed at a tumour molecular board. The primary endpoint was the proportion of patients who commenced targeted treatment based on cfDNA-NGS results without tissue molecular results, predicted to be ≥ 10%. RESULTS: Between April 2020-May 2021, 51 patients were enrolled; 49 were evaluable. The median age was 71 years, 43% were never-smokers, 86% had stage IV disease. 80% of evaluable cfDNA-NGS were informative (tumour-derived cfDNA detected). cfDNA-NGS detected 30 (61%) AMP/ASCO/CAP tier 1 variants, including 20 additional tier 1 variants compared to tissue testing. Three patients with non-informative cfDNA-NGS had tier 1 variants identified on tissue testing. Eleven (22%; 95%CI 12%-27%) patients commenced targeted therapy based on cfDNA-NGS results without tissue molecular results, meeting the primary endpoint. Median time to results was shorter for cfDNA-NGS compared to standard-of-care tissue tests (9 versus 25 days, P < 0.0001). CONCLUSION: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making.
RESUMEN
We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.