Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma.

Introduction: The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking. Materials and Methods: We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes. Results: Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype. Discussion: Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.

Network-Based Predictors of Progression in Head and Neck Squamous Cell Carcinoma.

The heterogeneity in head and neck squamous cell carcinoma (HNSCC) has made reliable stratification extremely challenging. Behavioral risk factors such as smoking and alcohol consumption contribute to this heterogeneity. To help elucidate potential mechanisms of progression in HNSCC, we focused on elucidating patterns of gene interactions associated with tumor progression. We performed de-novo gene co-expression network inference utilizing 229 patient samples from The Cancer Genome Atlas (TCGA) previously annotated by Bornstein et al. (2016). Differential network analysis allowed us to contrast progressor and non-progressor cohorts. Beyond standard differential expression (DE) analysis, this approach evaluates changes in gene expression variance (differential variability DV) and changes in covariance, which we denote as differential wiring (DW). The set of affected genes was overlaid onto the co-expression network, identifying 12 modules significantly enriched in DE, DV, and/or DW genes. Additionally, we identified modules correlated with behavioral measures such as alcohol consumption and smoking status. In the module enriched for differentially wired genes, we identified network hubs including IL10RA, DOK2, APBB1IP, UBASH3A, SASH3, CELF2, TRAF3IP3, GIMAP6, MYO1F, NCKAP1L, WAS, FERMT3, SLA, SELPLG, TNFRSF1B, WIPF1, AMICA1, PTPN22; the network centrality and progression specificity of these genes suggest a potential role in tumor evolution mechanisms related to inflammation and microenvironment. The identification of this network-based gene signature could be further developed to guide progression stratification, highlighting how network approaches may help improve clinical research end points and ultimately aid in clinical utility.

Deficiency of MIWI2 (Piwil4) induces mouse erythroleukemia cell differentiation, but has no effect on hematopoiesis in vivo.

Piwi proteins and their small non-coding RNA partners are involved in the maintenance of stem cell character and genome integrity in the male germ cells of mammals. MIWI2, one of the mouse Piwi-like proteins, is expressed in the prepachytene phase of spermatogenesis during the period of de novo methylation. Absence of this protein leads to meiotic defects and a progressive loss of germ cells. There is an accumulation of evidence that Piwi proteins may be active in hematopoietic tissues. Thus, MIWI2 may have a role in hematopoietic stem and/or progenitor cell self-renewal and differentiation, and defects in MIWI2 may lead to abnormal hematopoiesis. MIWI2 mRNA can be detected in a mouse erythroblast cell line by RNA-seq, and shRNA-mediated knockdown of this mRNA causes the cells to take on characteristics of differentiated erythroid precursors. However, there are no detectable hematopoietic abnormalities in a MIWI2-deficient mouse model. While subtle, non-statistically significant changes were noted in the hematopoietic function of mice without a functional MIWI2 gene when compared to wild type mice, our results show that MIWI2 is not solely necessary for hematopoiesis within the normal life span of a mouse.

Novel influenza A (H1N1) viral infection in pediatric patients with sickle-cell disease.

BACKGROUND: The 2009 novel influenza A (H1N1) pandemic has had profound public health implications all over the world. The majority of patients infected with the novel strain have recovered uneventfully. However, certain populations have been defined who appear to be at increased risk of complications due to H1N1 infections. This review summarizes the clinical course of five patients with sickle cell, four of whom had confirmed H1N1 infection, and one whom had a presumed H1N1 infection. PROCEDURE: The clinical presentation, hospital course, and treatment of five pediatric patients with sickle-cell disease and H1N1 infection were reviewed retrospectively. RESULTS: In this case series, our patients experienced complications such as the acute chest syndrome, acute marrow suppression of red cell production, pain crisis, and hematuria. CONCLUSIONS: In this population, who are at increased risk for bacterial superinfection as well as complications from the influenza virus itself, vigilance toward diagnosis and aggressive treatment will continue to be important as long as the novel virus is in circulation.

Isolated extramedullary relapse in childhood acute lymphocytic leukemia.

Although the vast majority of children with acute lymphocytic leukemia attain remission with modern therapies, an unacceptably high number will suffer a disease relapse. Both the duration of remission and the site of relapse are important prognostic factors. This review focuses on leukemic relapse isolated to sites outside the bone marrow (extramedullary sites). Data from cooperative study groups as well as large single institutions are reviewed with respect to the incidence of isolated extramedullary relapse as well as the outcome following relapse. The unique anatomic and physiologic properties of the testes and the central nervous system-the two most common sites of isolated extramedullary relapse-are discussed. Finally, the evolution of leukemia therapy is reviewed, bringing into focus the goals and challenges of future therapeutic endeavors.