||5R01CA204974-03 Interpret this number
||Children'S Hosp Of Philadelphia
||Structural Variation in Neuroblastoma
Neuroblastoma (NB) is a cancer of the developing sympathetic nervous system that most commonly affects
young children. Despite intense multi-modal therapy, the overall survival rate for high-risk NB remains less than
50%, and relapsed NB is almost universally incurable. Our long-term goal is to improve the outcome of children
with NB by defining the inherited and acquired genetic/genomic basis of the disease and response to therapy.
Structural variations (SVs) are changes in chromosomal architecture such as deletions, duplications,
translocations, and inversions. SVs can be inherited in the germline or acquired somatically, and have been
implicated in a wide array of human diseases, including cancer. While array-based approaches can identify large
scale copy number variation (CNV), whole-genome sequencing (WGS) enables characterization of many
complex SVs at base-pair resolution. Our objective here is to identify SVs associated with NB susceptibility,
malignant progression, and clonal evolution mediating therapy resistance that may be exploitable for risk
prediction and/or therapeutically. Our central hypothesis is that germline and somatic SVs potently influence
tumorigenesis and acquisition of therapy resistance in NB. The motivation for the proposed work is the need for
an integrated understanding of inherited genetic variation and acquired mutational events in the host and tumor
to enable improved risk assessment and develop rational, evidence-based therapies to improve patient
outcomes. We will test our hypothesis in three specific aims: 1) Identify rare germline SVs associated with NB
through a SV-based association study of 7,500 NB cases and 15,000 healthy children as controls and evaluation
of heritability in 642 patient-parent trios. 2) Discover and prioritize somatic SVs using whole genome-sequencing
(WGS) of 146 diagnostic NB pairs (tumor, germline), and 60 relapsed NB trios (diagnostic, relapsed and
germline). Recurrent and/or clonally enriched SVs will be prioritized using an integrative transcriptomic and
(epi)genomic approach and validated in two independent cohorts comprised of 1,158 NBs. 3) Characterize and
determine how genes influenced by recurrent SVs in NB drive tumorigenesis and the malignant phenotype. For
the final aim, a two-pronged approach is planned: 3a) a detailed in silico molecular characterization of SVs and
genes transcriptionally altered by SVs using matched germline and tumor data from 646 primary patient samples
(germline/tumor whole genome sequencing, DNA copy number, DNA methylation, and mRNA/miRNA
expression) and 3b) genetic manipulation of candidate genes and/or genome-editing of prioritized SV loci in a
highly characterized panel of NB cell lines to define biological significance and begin to understand underlying
mechanisms of tumorigenesis. This work will have a sustained and positive impact on the field by providing
substantial insights into genetic predisposition, malignant progression, and the relapsed genome of this important
childhood cancer. Ultimately, this knowledge has the potential to inform the development of clinical biomarkers
and/or novel, evidence-based therapies to improve outcomes of children with NB, and possibly other cancers.
Genetic susceptibility to neuroblastoma: current knowledge and future directions.
, Randall M.P.
, Bosse K.R.
, Diskin S.J.
Cell And Tissue Research, 2018-03-27 00:00:00.0; , .
Neuroblastoma Survivors Are At Increased Risk For Second Malignancies: A Report From The International Neuroblastoma Risk Group Project
, Vaksman Z.
, Lee S.M.
, Hungate E.A.
, Henderson T.O.
, London W.B.
, Pinto N.
, Volchenboum S.L.
, Park J.R.
, Naranjo A.
, et al.
European Journal Of Cancer (oxford, England : 1990), 2016-12-26 00:00:00.0; 72, p. 177-185.