Copy number variation at 1q21.1 associated with neuroblastoma

Abstract

Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in cancer, we performed a genome-wide association study (GWAS) of CNVs in the childhood cancer neuroblastoma, a disease where SNP variations are known to influence susceptibility 1,2 . We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Supplementary Information is linked to the online version of the paper at www.nature.com/nature Author Contributions S.J.D and J.M.M. designed the study and drafted the manuscript. C.H., C.K., and H.H. performed the genotyping. S.J.D. analyzed SNP data and performed CNV association study. J.B., S.F.A.G., H.H., and H.L. performed the corrections for population stratification. S.J.D., E.F.A. and Y.P.M. analyzed and interpreted SNP data for tumor specimens. K.W. and S.J.D. analyzed SNP data for second replication set. J.G. analyzed SNP data from trios for inheritance estimates. C.H., S.J.D., A.W. and E.R.R. performed and/or analyzed qPCR experiments. E.A.G., K.C., and T.H.S. performed FISH experiments. S.J.D., M.L., K.B., K.P., M.D, and E.R.R. designed and/or performed experiments to identify and sequence transcript within 1q21.1 CNV. J.E.L., C.W., S.J.D. and E.R.R. performed and/or analyzed expression experiments. P.M. and W.L. analyzed clinical covariates. A.I.B. provided detailed endpoints for 1q21.1 CNV in an independent analysis of healthy controls using a custom high-resolution Agilent array. M.D., H.L., and HH contributed to overall GWAS study design. All authors commented on or contributed to the current manuscript. Author InformationThe authors declare no competing interests. Correspondence and requests for materials should be addressed to J.M.M. (maris@chop.edu). Caucasian controls at 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. We identified a common CNV at 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets (P combined = 2.97 × 10 −17 ; OR = 2.49, 95% CI: 2.02 to 3.05). This CNV was validated by quantitative PCR, fluorescent in situ hybridization, and analysis of matched tumor specimens, and was shown to be heritable in an independent set of 713 cancer-free trios. We identified a novel transcript within the CNV which showed high sequence similarity to several "Neuroblastoma breakpoint family" (NBPF) genes 3,4 and represents a new member of this gene family (NBPFX). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a novel NBPF gene in early tumorigenesis of th...

Overview and recent advances in the treatment of neuroblastoma

“…Genome-wide association studies (GWAS) have also identified additional germline genetic variants in neuroblastoma patients, including single-nucleotide polymorphisms in LIN28B, BARD1, and LMO1, among others [26][27][28][29] as well as other polymorphisms in other chromosomal regions yet to be fully characterized [30,31]. These polymorphisms occur relatively frequently in the general population and may contribute to the development of sporadic neuroblastoma, although the functional roles of these germline variants and other somatic alterations remain to be elucidated.…”

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

“…Emerging insights into the genetics of constitutional disease etiology demonstrate that germ line polymorphisms in the form of copy number variants (CNVs) (3,4), both de novo and inherited, are associated with diseases, including Alzheimer's, Parkinson, mental retardation, autism, and schizophrenia (5). CNVs also confer risk to developing cancers, such as neuroblastoma, and are enriched in Li-Fraumeni syndrome (6,7). Therefore, given the strong heritable nature of prostate cancer, we sought to detect clinically-informative prostate cancer risk CNVs in the setting of widespread prostate-specific antigen (PSA) screening, as practiced in the United States (8) and Western Europe (9).…”

Genome-wide association analysis of copy number variations in subarachnoid aneurysmal hemorrhage

“…17,22 This program has been widely used by researchers and the results generated from the program are already publicized in papers. [22][23][24][25][26][27] Two other ways of verifying the accuracy of the identified CNVs involve comparing the results with the DGV databases in which information on previously reported CNVs is stored, or using another CNV identification program to compare the results with.…”