Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital ...mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours ...encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
The driver landscape of sporadic chordoma Tarpey, Patrick S; Behjati, Sam; Young, Matthew D ...
Nature communications,
10/2017, Letnik:
8, Številka:
1
Journal Article
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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.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
Childhood tumors that occur synchronously in different anatomical sites usually represent metastatic disease. However, such tumors can be independent neoplasms. We investigated whether cases of ...bilateral neuroblastoma represented independent tumors in two children with pathogenic germline mutations by genotyping somatic mutations shared between tumors and blood. Our results suggested that in both children, the lineages that had given rise to the tumors had segregated within the first cell divisions of the zygote, without being preceded by a common premalignant clone. In one patient, the tumors had parallel evolution, including distinct second hits in
, a putative predisposition gene for neuroblastoma. These findings portray cases of bilateral neuroblastoma as having independent lesions mediated by a germline predisposition. (Funded by Children with Cancer UK and Wellcome.).
Case 1-an embryonal rhabdomyosarcoma-had a canonical NRAS Gln61Arg mutation, which is a known variant of embryonal rhabdomyosarcoma.2 Case 2-a lymphocytic neoplasm-had a canonical mutation in NOTCH1, ...which is an established cancer gene of haematological malignancies.3 Case 3-a cellular capillary haemangioma-had an ASXL1 nonsense mutation. References 1 DM Carrick, MG Mehaffey, MC Sachs, Robustness of next generation sequencing on older formalin-fixed paraffin-embedded tissue, PloS One, Vol. 10, 2015, e0127353 2 Y Chen, J Takita, M Hiwatari,...
Spatio-temporal immune zonation of the human kidney Stewart, Benjamin J; Ferdinand, John R; Young, Matthew D ...
Science (American Association for the Advancement of Science),
09/2019, Letnik:
365, Številka:
6460
Journal Article
Recenzirano
Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly, or via crosstalk with immune cells. We used single cell RNA ...sequencing to resolve the spatio-temporal immune topology of the human kidney. We reveal anatomically-defined expression patterns of immune genes within the epithelial compartment, with anti-microbial peptide transcripts evident in pelvic epithelium in the mature, but not fetal kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with post-natal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune crosstalk orchestrated localization of anti-bacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell ...transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
Spatiotemporal immune zonation of the human kidney Stewart, Benjamin J; Ferdinand, John R; Young, Matthew D ...
Science (American Association for the Advancement of Science),
09/2019, Letnik:
365, Številka:
6460
Journal Article
Recenzirano
Odprti dostop
Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA ...sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
Purpose: Although the importance of genetics education for health care professionals is increasingly recognized worldwide, little is known about the needs and views of nongenetics postgraduate ...medical trainees.
Methods: Data on the views of 143 learners from four specialties (family practice, neurology, cardiology, and dermatology) in two regions in England (West Midlands and South Western) were collected using focus groups, questionnaires, and interviews.
Results: Low levels of genetics training were reported by both trainee family practitioners and trainee hospital consultant specialists. Responses to attitude statements indicate that the majority of trainee family practitioners believed genetics was important but thought that they were underprepared in this area. Focus groups with specialty trainees revealed general consensus that there was not enough formal postgraduate genetics training, although some cardiologists disagreed and trainees in all three specialties thought that the existing curriculum was overcrowded. Trainees stressed the importance of tailoring genetics education to be directly relevant to their daily practice. Trainee family practitioners prioritized topics related to the identification and referral of patients, and the subsequent implication of results. In contrast, specialty trainees prioritized topics related to the genetics and management of particular diseases.
Conclusion: There is still work to be done before trainees in nongenetics specialties recognize how genetics can be relevant to their practice. Involvement of specialty trainers in the development and delivery of genetics education may help to address this issue.
1 Educational tool and point-of-care tests to assist antibiotic prescribing decisions for diabetic foot ulcer infections (INDUCE study) John Ingram1, Scott Cawley2, Angela Jones2, Elinor Coulman3, ...Clive Gregory4, Tim Pickles3 1Department of Dermatology and Academic Wound Healing, Division of Infection & Immunity, Cardiff University, Cardiff, UK; 2Podiatry Department, Cardiff and Vale University Health Board, Cardiff, UK; 3Centre for Trials Research, Cardiff University, Cardiff, UK; 4Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK Correspondence: Angela Jones Background Assessing diabetic foot ulcers (DFUs) for infection is difficult because clinical symptoms and signs may be masked by neuropathy and vasculopathy and there are no objective tests available at point of care to guide clinicians. Calprotectin in wound exudate may have value, but only in combination with other biomarkers. 2 Shoe hardness and gait Him Shun Hinson Kei, Paul Fletcher, Mike Curran Faculty of Health and Society, University of Northampton, Northampton, UK Correspondence: Him Shun Hinson Kei Introduction This study will have implications for any healthcare professionals who aim to alter patient’s gait with footwear. Comparison of a commercially available rowing specific shoe to a training shoe Trevor Prior Centre for Sports and Exercise Medicine, William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK Background In the sport of rowing, load applied through the feet must be efficiently and effectively translated into propulsive force at the oar. By contrast, the rowing shoe focussed the force beneath the 1st Met head and, due to the reduced contact area, resulted in a greater peak pressures. 4 Importance of accurate identification of arterial perfusion using different physiological tests Cynthia Formosa Faculty of Health Sciences, University of Malta, Msida, Malta Background Although diagnostic and therapeutic decisions in patients with peripheral
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