Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Early morbidities following paediatric cardiac surgery: a mixed-methods study

Background: Over 5000 paediatric cardiac surgeries are performed in the UK each year and early survival has improved to > 98%. Objectives: We aimed to identify the surgical morbidities that present the greatest burden for patients and health services and to develop and pilot routine monitoring and feedback. Design and setting: Our multidisciplinary mixed-methods study took place over 52 months across five UK paediatric cardiac surgery centres. Participants: The participants were children aged < 17 years. Methods: We reviewed existing literature, ran three focus groups and undertook a family online discussion forum moderated by the Children’s Heart Federation. A multidisciplinary group, with patient and carer involvement, then ranked and selected nine key morbidities informed by clinical views on definitions and feasibility of routine monitoring. We validated a new, nurse-administered early warning tool for assessing preoperative and postoperative child development, called the brief developmental assessment, by testing this among 1200 children. We measured morbidity incidence in 3090 consecutive surgical admissions over 21 months and explored risk factors for morbidity. We measured the impact of morbidities on quality of life, clinical burden and costs to the NHS and families over 6 months in 666 children, 340 (51%) of whom had at least one morbidity. We developed and piloted methods suitable for routine monitoring of morbidity by centres and co-developed new patient information about morbidities with parents and user groups. Results: Families and clinicians prioritised overlapping but also different morbidities, leading to a final list of acute neurological event, unplanned reoperation, feeding problems, renal replacement therapy, major adverse events, extracorporeal life support, necrotising enterocolitis, surgical infection and prolonged pleural effusion. The brief developmental assessment was valid in children aged between 4 months and 5 years, but not in the youngest babies or 5- to 17-year-olds. A total of 2415 (78.2%) procedures had no measured morbidity. There was a higher risk of morbidity in neonates, complex congenital heart disease, increased preoperative severity of illness and with prolonged bypass. Patients with any morbidity had a 6-month survival of 81.5% compared with 99.1% with no morbidity. Patients with any morbidity scored 5.2 points lower on their total quality of life score at 6 weeks, but this difference had narrowed by 6 months. Morbidity led to fewer days at home by 6 months and higher costs. Extracorporeal life support patients had the lowest days at home (median: 43 days out of 183 days) and highest costs (£71,051 higher than no morbidity). Limitations: Monitoring of morbidity is more complex than mortality, and hence this requires resources and clinician buy-in. Conclusions: Evaluation of postoperative morbidity provides important information over and above 30-day survival and should become the focus of audit and quality improvement. Future work: National audit of morbidities has been initiated. Further research is needed to understand the implications of feeding problems and renal failure and to evaluate the brief developmental assessment. Funding: This project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 30. See the NIHR Journals Library website for further project information

Orolabial signs are important clues for diagnosis of the rare endocrine syndrome MEN 2B. Presentation of two unrelated cases

Multiple endocrine neoplasia syndromes (MEN) are genetic disorders with glandular hyperplasia and consecutive malignant neoplasia. MEN type 2B is the least common form of these tumor syndromes. It presents with typical dysmorphic features, mucosal neuromas, ganglioneuromatosis, medullary thyroid carcinoma (MTC) and phaeochromocytoma. The prognosis depends on the presence of MTC. We have surprisingly found two unrelated patients with this syndrome at our department within two weeks. In the medical history of a 17-year-old boy, Crohn's disease had been considered because of abdominal pain and distention. He had marfanoid appearance and previously undergone minor surgeries for a large tongue with neuromas and hypertrophic gums. Two weeks later, a 10-year-old girl presented with a hard palpable mass on her neck. She had thickened lips, neuromas on the tongue and a solitary thyroid nodule. Genetic analysis was carried out in both patients and a heterozygous M918T mutation of the RET proto-oncogene was found. Laboratory tests and imaging studies were consistent with MTC. Phaeochromocytoma was not present. Both patients underwent total thyroidectomy and lymph node dissection. Histological examination confirmed the diagnosis of MTC. In conclusion, the initial diagnosis of MEN 2B should be suspected on the presence of typical facial/oral signs and gastrointestinal symptoms. Hormonal tests and imaging techniques of the thyroid and the adrenals can confirm the clinical diagnosis of MEN 2B and genetic analysis can prove its germline origin