The driver landscape of sporadic chordoma

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma

Supporting genetics in primary care: investigating how theory can inform professional education

Evidence indicates that many barriers exist to the integration of genetic case finding into primary care. We conducted an exploratory study of the determinants of three specific behaviours related to using breast cancer genetics referral guidelines effectively: 'taking a family history', 'making a risk assessment', and 'making a referral decision'. We developed vignettes of primary care consultations with hypothetical patients, representing a wide range of genetic risk for which different referral decisions would be appropriate. We used the Theory of Planned Behavior to develop a survey instrument to capture data on behavioural intention and its predictors (attitude, subjective norm, and perceived behavioural control) for each of the three behaviours and mailed it to a sample of Canadian family physicians. We used correlation and regression analyses to explore the relationships between predictor and dependent variables. The response rate was 96/125 (77%). The predictor variables explained 38-83% of the variance in intention across the three behaviours. Family physicians' intentions were lower for 'making a risk assessment' (perceived as the most difficult) than for the other two behaviours. We illustrate how understanding psychological factors salient to behaviour can be used to tailor professional educational interventions; for example, considering the approach of behavioural rehearsal to improve confidence in skills (perceived behavioural control), or vicarious reinforcement as where participants are sceptical that genetics is consistent with their role (subjective norm)

The Dawning Era of Personalized Medicine Exposes a Gap in Medical Education

Medical student Keyan Salari argues that it is crucial that medical students be trained to use and interpret patients' genetic information appropriately and responsibly

A toolkit for incorporating genetics into mainstream medical services: Learning from service development pilots in England

Background: As advances in genetics are becoming increasingly relevant to mainstream healthcare, a major challenge is to ensure that these are integrated appropriately into mainstream medical services. In 2003, the Department of Health for England announced the availability of start-up funding for ten 'Mainstreaming Genetics' pilot services to develop models to achieve this. Methods: Multiple methods were used to explore the pilots' experiences of incorporating genetics which might inform the development of new services in the future. A workshop with project staff, an email questionnaire, interviews and a thematic analysis of pilot final reports were carried out. Results: Seven themes relating to the integration of genetics into mainstream medical services were identified: planning services to incorporate genetics; the involvement of genetics departments; the establishment of roles incorporating genetic activities; identifying and involving stakeholders; the challenges of working across specialty boundaries; working with multiple healthcare organisations; and the importance of cultural awareness of genetic conditions. Pilots found that the planning phase often included the need to raise awareness of genetic conditions and services and that early consideration of organisational issues such as clinic location was essential. The formal involvement of genetics departments was crucial to success; benefits included provision of clinical and educational support for staff in new roles. Recruitment and retention for new roles outside usual career pathways sometimes proved difficult. Differences in specialties' working practices and working with multiple healthcare organisations also brought challenges such as the 'genetic approach' of working with families, incompatible record systems and different approaches to health professionals' autonomous practice. 'Practice points' have been collated into a Toolkit which includes resources from the pilots, including job descriptions and clinical tools. These can be customised for reuse by other services. Conclusions: Healthcare services need to translate advances in genetics into benefits for patients. Consideration of the issues presented here when incorporating genetics into mainstream medical services will help ensure that new service developments build on the body of experience gained by the pilots, to provide high quality services for patients with or at risk of genetic conditions

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis ⩽40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms

Nevoid Basal Cell Carcinoma Syndrome

CLINICAL CHARACTERISTICS:Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years. Life expectancy in NBCCS is not significantly different from average. DIAGNOSIS/TESTING:The diagnosis of NBCCS is established in a proband who fulfills existing diagnostic clinical criteria. Identification of a heterozygous germline pathogenic variant in PTCH1 or SUFU on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. MANAGEMENT:Treatment of manifestations: Best provided by specialists experienced with the condition; keratocysts usually require surgical excision; early treatment of BCCs to ensure complete eradication of aggressive BCCs and to preserve normal tissue to prevent disfigurement; sonic hedgehog inhibitors such as vismodegib to treat severe BCCs; preservation of ovarian tissue whenever ovarian fibromas require surgical treatment. However, the cost of treatment has meant that the National Institute for Health and Care Excellence in the UK has judged the treatment not cost effective. Prevention of primary manifestations: Avoidance of direct sun exposure through the use of complete sunblock and covering of exposed skin with long sleeves, high collars, and hats. Surveillance: Monitoring of head circumference throughout childhood; developmental assessment and physical examination every six months in the first years of life because of increased risk for medulloblastoma; in those older than age eight years, orthopantogram every 12-18 months to identify jaw keratocysts; skin examination at least annually. Agents/circumstances to avoid: Radiotherapy if there are alternative treatments, especially in childhood; diagnostic x-rays should be used sparingly; direct sun exposure should be limited; excessive sun exposure increases the likelihood of developing BCCs. Evaluation of relatives at risk: Because of the need for surveillance for complications of NBCCS (medulloblastoma in children; jaw cysts and BCCs in adults) and the need to avoid sun exposure, clarification of the genetic status of at-risk relatives, including children, is appropriate. GENETIC COUNSELING:NBCCS is inherited in an autosomal dominant manner. Approximately 70%-80% of individuals with NBCCS have an affected parent and about 20%-30% have NBCCS as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting NBCCS. Prenatal testing for pregnancies at risk is possible if the PTCH1 or SUFU pathogenic variant has been identified in an affected family member

Linkage data for Marfan syndrome and markers on chromosomes 1 and 11.

Six large families with classical Marfan syndrome were studied using markers on chromosomes 1 and 11. Two of three families tested showed negative scores using D1S7 but a third family gave a positive score (0.92) at theta = 0.1. The other chromosome 1 markers typed (MUCI, NGFB, D1S8) excluded close linkage. Negative lod scores with two chromosome 11q22 markers (D11S84, D11S148) excluded at least 20 cM in this area (Z = less than -2), which was chosen for study as two enzymes responsible for collagen degradation (collagenase and stromelysin) are localised to this region