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Devoto M.,Childrens 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.

Lombardi C.,University of California at Los Angeles | Ganguly A.,University of Pennsylvania | Bunin G.R.,Center for Childhood Cancer Research | Azary S.,University of California at Los Angeles | And 3 more authors.
Cancer Causes and Control | Year: 2015

Purpose: Previous studies have suggested a role for parental diet in childhood cancer prevention, but there are few studies of retinoblastoma. The aim of this study was to examine the relation between maternal diet and unilateral retinoblastoma. Methods: A case–control study of 163 unilateral RB cases and 136 controls ascertained information on maternal diet during pregnancy using a standardized food frequency questionnaire. Logistic regression was used to assess the relation between retinoblastoma and food groups and dietary patterns. Results: We observed a negative association between retinoblastoma and intake of fruit [odds ratio (OR) 0.38, 95 % confidence interval (CI) 0.14–1.02]. Positive associations were seen with intake of cured meats (OR 5.07, 95 % CI 1.63–15.70) and fried foods (OR 4.89, 95 % CI 1.72–13.89). A food pattern of high fruits and vegetables and low fried food and sweets was negatively associated with disease (OR 0.75, 95 % CI 0.61–0.92). Conclusion: Our study provides preliminary evidence that mothers who consume diets higher in fruit and lower in fried foods and cured meats during pregnancy may reduce the risk of unilateral retinoblastoma in their offspring. © 2014, Springer International Publishing Switzerland.

Dews M.,Center for Childhood Cancer Research | Tan G.S.,Center for Childhood Cancer Research | Hultine S.,Center for Childhood Cancer Research | Raman P.,Childrens 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.

Rupp L.J.,Center for Childhood Cancer Research | Rupp L.J.,University of Pennsylvania | Chen L.,Duke University | Krangel M.S.,Duke University | And 2 more authors.
Methods in Molecular Biology | Year: 2016

PCR on genomic DNA isolated from lymphocyte populations is an invaluable technique to analyze T cell receptor (TCR) α and β gene rearrangements. Although this approach is powerful, it also has limitations that must be accounted for in experimental design and data interpretation. Here, we provide background required for understanding these limitations, and then outline standard PCR methods that can be used for analysis of TCR α and β gene rearrangements in mice. © Springer Science+Business Media New York 2016.

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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