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PMID: 22941191 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.

Nature genetics ·Vol. 44 ·No. 10 ·2012-10-00 ·Pages 1126-30

Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, Diamond M, Carpenter EL, Winter C, Lee H, Jagannathan J, Latorre V, Iolascon A, Hakonarson H, Devoto M, Maris JM

Abstract

Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P=2.7×10(-11); odds ratio 1.26, 95% confidence interval (CI) 1.18-1.35) and the second within LIN28B (rs17065417; combined P=1.2×10(-8); odds ratio 1.38, 95% CI 1.23-1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P=0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.

MeSH Terms
Case-Control Studies Cell Line, Tumor Cell Proliferation Chromosomes, Human, Pair 6 Cohort Studies DNA-Binding Proteins/genetics,metabolism Gene Expression Gene Frequency Gene Knockdown Techniques Genetic Predisposition to Disease Genome-Wide Association Study Humans Infant Kaplan-Meier Estimate Linkage Disequilibrium Neuroblastoma/genetics,metabolism,mortality Oligonucleotide Array Sequence Analysis Polymorphism, Single Nucleotide RNA Interference RNA-Binding Proteins Sequence Analysis, DNA Transcriptome Ubiquitin-Protein Ligases/genetics,metabolism
Chemicals
DNA-Binding Proteins LIN28B protein, human RNA-Binding Proteins HACE1 protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Diskin Sharon J
Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Capasso Mario
Schnepp Robert W
Cole Kristina A
Attiyeh Edward F
Hou Cuiping
Diamond Maura
Carpenter Erica L
Winter Cynthia
Lee Hanna
Jagannathan Jayanti
Latorre Valeria
Iolascon Achille
Hakonarson Hakon
Devoto Marcella
Maris John M
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2387
Published
2012-10-00
Epub
2012-00-02
Pages
1126-30
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3459292
Subset
IM
Grants
NCI NIH HHS · R01-CA124709 · United States
NCI NIH HHS · K08-CA136979 · United States
NICHD NIH HHS · P30 HD026979 · United States
NCI NIH HHS · R01 CA124709 · United States
NCI NIH HHS · K99-CA151869 · United States
NICHD NIH HHS · P30-HD026979 · United States
NCI NIH HHS · K99 CA151869 · United States
NCI NIH HHS · R00 CA151869 · United States
NCI NIH HHS · K08 CA136979 · United States
External Links
PubMed source DOI: 10.1038/ng.2387 PMC Full Text View journal details
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