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Devoto M.,Children's Hospital of Philadelphia | Devoto M.,University of Pennsylvania | Devoto M.,University of Rome La Sapienza | Specchia C.,University of Brescia | And 5 more authors.
Human Heredity | Year: 2011

Background: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB. Methods: To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations. Results: The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance. Conclusions: This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases. Copyright © 2011 S. Karger AG, Basel.

News Article | December 20, 2016

Scientists have used systems biology tools to map out molecular pathways and signaling circuits that come into play when the immune system acts against infections and cancer. Important immune cells, called CD8+ T cells, play a pivotal role in immune response, but their gene regulatory circuits are not well understood. Researchers from Children's Hospital of Philadelphia (CHOP) and the University of Iowa used sophisticated sequencing and computational techniques to investigate the molecular mechanisms during each stage of the CD8+ T cells' responses. By identifying novel biological pathways and publishing details of these interactions, the study team aims to help uncover useful targets in developing better vaccines and cancer treatments. "We have revealed novel components and connections in the regulatory network underlying how these T cells mount an immune response," said study co-leader Kai Tan, PhD, of the Center for Childhood Cancer Research and the Departments of Pediatrics and Biomedical and Health Informatics at CHOP. "We found highly dynamic processes as these cells develop. In addition to adding to our knowledge of cell biology, these findings may help advance vaccine development and cancer immunotherapy." Tan and colleagues at CHOP co-authored the study with a team led by Hai-Hui Xue, MD, PhD, of the Carver College of Medicine at the University of Iowa. The research appeared online Dec. 13 in Immunity and in print today. The researchers investigated how CD8+ T cells in laboratory mice respond to infections. In mice, humans and other mammals, those cells begin in a naïve pre-infected state, but after encountering an antigen, differentiate into large quantities of effector cells to clear an infection. After the infection, cell numbers diminish, but central memory T cells retain a long-term ability to defend against reinfection by microorganisms that carry the same antigen. The three stages of CD8+ T cell development are well known, but the current study identifies a detailed map of the regulatory circuitry, such as interactions between enhancers and promoters--genetic regulatory regions that function together in driving genes to transcribe proteins to carry out biological processes. Using bioinformatics tools to identify and map out specific components and regulatory interconnections, the study team found highly dynamic activities during CD8+ T cell responses: a distinct repertoire of super enhancers -- groups of enhancers that interact with promoters to drive gene transcription, new groups of enhancers that jump into activity only in the memory cell stage, and extensive re-wiring of regulatory circuits from one cell stage to another. "Better understanding of these mechanisms is important because increasing the quantity and quality of memory CD8+ T cells is a key goal in developing more effective vaccines and immunotherapeutic strategies," said Tan. "In addition, although many shared properties exist between infection and cancer, future studies identifying distinct regulatory wiring in cancer-infiltrating T cells are essential for the continued progress of cancer immunotherapy." The researchers created a website to hold datasets resulting from this study, including a "roadmap" of methods for extracting useful clues for further study by other researchers. "We expect this resource will suggest novel targets for researchers in immunology and oncology," said Tan. He added that the immediate next step is to perform experimental testing and refining of the circuit models from this study. Primary support for this study came from the National Institutes of Health (grant AI115149), with additional support from 10 other NIH grants to various co-authors. The co-first authors are Bing He, PhD, from CHOP, and Shaojun Xing, PhD, from the University of Iowa. Bing He et al, "CD8+M/sup> T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections," Immunity, published online Dec. 13, 2016, in print Dec.20. http://doi. About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.

Dews M.,Center for Childhood Cancer Research | Tan G.S.,Center for Childhood Cancer Research | Hultine S.,Center for Childhood Cancer Research | Raman P.,Children's Hospital of Philadelphia | And 7 more authors.
Journal of the National Cancer Institute | Year: 2014

Background The c-Myc oncoprotein is activated in the majority of colorectal cancers (CRCs), whereas the TGF-β pathway is frequently affected by loss-of-function mutations, for example in SMAD2/3/4 genes. The canonical model places Myc downstream of inhibitory TGF-β signaling. However, we previously demonstrated that Myc also inhibits TGF-β signaling through the miR-17∼92 microRNA cluster, raising the question about functional relationships between these two pathways. Methods We engineered a series of genetically complex murine and human CRC cell lines in which Myc and TGF-β activities could be manipulated simultaneously. This was achieved through retroviral expression of the Myc-estrogen receptor fusion protein and through Smad4 short hairpin RNA knockdown. Cell lines thus modified were injected subcutaneously in immunocompromised mice, and the resultant tumors (n = 5-10 per treatment group) were analyzed for overall growth and neovascularization. Additionally, the distribution of MYC and TGF-β pathway mutations was analyzed in previously profiled human CRC samples. Results In kras-mutated/trp53-deleted murine colonocytes, either Myc activation or TGF-β inactivation increased tumor sizes and microvascular densities approximately 1.5-to 2.5-fold, chiefly through downregulation of thrombospondin-1 and related type I repeat-containing proteins. Combining Myc activation with TGF-β inactivation did not further accelerate tumorigenesis. This redundancy and the negative effect of TGF-β signaling on angiogenesis were also demonstrated using xenografts of human CRC cell lines. Furthermore, the analysis of the Cancer Genome Atlas data revealed that in CRC without microsatellite instability, overexpression of Myc and inactivation of Smads (including acquired mutations in SMAD2) are mutually exclusive, with odds ratio less than 0.1. Conclusions In human CRC, gain-of-function alterations in Myc and loss-of-function alterations in TGF-β exhibit a masking epistatic interaction and are functionally redundant. © The Author 2014. Published by Oxford University Press. All rights reserved.

Fox J.L.,Center for Childhood Cancer Research | Fox J.L.,University of Pennsylvania | Dews M.,Center for Childhood Cancer Research | Minn A.J.,University of Pennsylvania | And 2 more authors.
RNA | Year: 2013

The miR-17~92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17~92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17~92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels. Interestingly, it also reduces the levels of CTGF primary transcript. The unexpected effects of miR-18a on CTGF transcription are mediated in part by direct targeting of Smad3 and ensuing weakening of TGFβ signaling. Having defined the TGFβ signature in GBM cells, we demonstrate a significant anti-correlation between miR-18 and TGFβ signaling in primary GBM samples from The Cancer Genome Atlas. Most importantly, high levels of miR-18 combined with low levels of the TGFβ metagene correlate with prolonged patient survival. Thus, low expression of the miR-17~92 cluster, and specifically miR-18a, could significantly contribute to GBM pathogenesis. Copyright © 2013 RNA Society.

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