Project Title: Copy number variations (CNVs) in neuroblastoma Project Summary: Neuroblastoma remains one of the most deadly cancers in children with an overall survival rate for high-risk disease less than 40% despite intensive multi-modal therapy. A deeper understanding of the genetics and biology driving neuroblastoma tumorigenesis may reveal important genes and/or pathways to be targeted therapeutically and will pave the way for molecular diagnostic testing and personalized medicine. We hypothesize that both common and rare copy number variations (CNVs) also influence the genesis of neuroblastoma and that they mark critical genomic regions where somatic alterations and/or mutations occur in primary tumors. This proposal seeks to identify genes important to initiation and progression of neuroblastoma by achieving the following specific aims 1) Identify common constitutional CNVs associated with neuroblastoma through a CNV-based GWAS of 5,000 neuroblastoma cases and 10,000 healthy children as controls. 2) Identify rare constitutional CNVs affecting genes enriched in relevant functional categories and/or pathways associated with neuroblastoma, also utilizing data generated as part of our GWAS effort. 3) Characterize and determine biological relevance of genes influenced by neuroblastoma-associated CNVs. Here, a two-pronged approach is proposed a) a detailed integrative molecular characterization using matched germline and tumor specimens (germline/tumor whole genome sequencing, DNA copy number, DNA methylation, and mRNA/miRNA expression) of all genes directly influenced by neuroblastoma-associated CNVs. b) confirm biological relevance of NBPF23 and NME7, two genes we have demonstrated to be influenced by neuroblastoma-associated CNVs, using molecular biological techniques applied to both developing sympathetic nervous tissue and a large set of annotated tumor tissues. The discoveries generated from this effort will provide substantial insight into both genetic predisposition as well as malignant progression of this important childhood cancer, and will provide the first functional characterization of genes influenced by CNV in neuroblastoma. Discoveries from this study are likely to have broader implications to cancer biology and cancer predisposition. This proposal lays out a 5-year research plan. The first 2-years include a detailed research and training program that will prepare the PI for transition to the independent phase starting year 3 with the goal of obtaining R01 funding prior to year 5. Her mentors and advisors are leaders in the fields of neuroblastoma research, biostatistics, cancer genetics/genomics, and translational research. She will take advantage of the extensive resources of her environment, both at the Children's Hospital of Philadelphia, and the University of Pennsylvania.
Neuroblastoma is the most common extra-cranial solid tumor of childhood and is often lethal. Understanding the genetic events, such as copy number variation (CNV), that drive neuroblastoma tumorigenesis will have considerable relevance to the health of children with this disease as these events may identify molecular pathways critical to the malignant phenotype and thus exploitable therapeutically. Furthermore and as demonstrated in the past, the genes involved in predisposition to neuroblastoma may provide substantial insight into normal human development and cancer biology in general.
|Jiang, Yuchao; Oldridge, Derek A; Diskin, Sharon J et al. (2015) CODEX: a normalization and copy number variation detection method for whole exome sequencing. Nucleic Acids Res 43:e39|
|Oldridge, Derek A; Wood, Andrew C; Weichert-Leahey, Nina et al. (2015) Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528:418-21|
|Schnepp, Robert W; Khurana, Priya; Attiyeh, Edward F et al. (2015) A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis. Cancer Cell 28:599-609|
|Diskin, Sharon J; Capasso, Mario; Diamond, Maura et al. (2014) Rare variants in TP53 and susceptibility to neuroblastoma. J Natl Cancer Inst 106:dju047|
|Capasso, Mario; Diskin, Sharon J; Totaro, Francesca et al. (2013) Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis 34:605-11|
|Gamazon, Eric R; Pinto, Navin; Konkashbaev, Anuar et al. (2013) Trans-population analysis of genetic mechanisms of ethnic disparities in neuroblastoma survival. J Natl Cancer Inst 105:302-9|
|Diskin, Sharon J; Capasso, Mario; Schnepp, Robert W et al. (2012) Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet 44:1126-30|
|Latorre, Valeria; Diskin, Sharon J; Diamond, Maura A et al. (2012) Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol Biomarkers Prev 21:658-63|
|Bosse, Kristopher R; Diskin, Sharon J; Cole, Kristina A et al. (2012) Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res 72:2068-78|
|Nguyen, Le B; Diskin, Sharon J; Capasso, Mario et al. (2011) Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet 7:e1002026|
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