Integrative genomics identifies LMO1 as a neuroblastoma oncogene.
Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 × 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P < 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Kai
K
Wang
Sharon J
SJ
Diskin
Haitao
H
Zhang
Edward F
EF
Attiyeh
Cynthia
C
Winter
Cuiping
C
Hou
Robert W
RW
Schnepp
Maura
M
Diamond
Kristopher
K
Bosse
Patrick A
PA
Mayes
Joseph
J
Glessner
Cecilia
C
Kim
Edward
E
Frackelton
Maria
M
Garris
Qun
Q
Wang
Wendy
W
Glaberson
Rosetta
R
Chiavacci
Le
L
Nguyen
Jayanti
J
Jagannathan
Norihisa
N
Saeki
Hiroki
H
Sasaki
Struan F A
SF
Grant
Achille
A
Iolascon
Yael P
YP
Mosse
Kristina A
KA
Cole
Hongzhe
H
Li
Marcella
M
Devoto
Patrick W
PW
McGrady
Wendy B
WB
London
Mario
M
Capasso
Nazneen
N
Rahman
Hakon
H
Hakonarson
John M
JM
Maris
D000483:Alleles; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005060:Europe / Q000208:ethnology; D020440:Gene Duplication / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D060588:LIM Domain Proteins; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D009857:Oncogenes / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C065072:LMO1 protein, human; D014157:Transcription Factors