Integrative genomics identifies LMO1 as a neuroblastoma oncogene

被引：246

作者：

Wang, Kai ^{[1
]}

Diskin, Sharon J. ^{[2
,3
]}

Zhang, Haitao ^{[1
]}

Attiyeh, Edward F. ^{[2
,3
]}

Winter, Cynthia ^{[2
,3
]}

Hou, Cuiping ^{[1
]}

Schnepp, Robert W. ^{[2
,3
]}

Diamond, Maura ^{[2
,3
]}

Bosse, Kristopher ^{[2
,3
]}

Mayes, Patrick A. ^{[2
,3
]}

Glessner, Joseph ^{[1
]}

Kim, Cecilia ^{[1
]}

Frackelton, Edward ^{[1
]}

Garris, Maria ^{[2
,3
]}

Wang, Qun ^{[2
,3
]}

Glaberson, Wendy ^{[1
]}

Chiavacci, Rosetta ^{[1
]}

Nguyen, Le ^{[2
,3
,4
,6
]}

Jagannathan, Jayanti ^{[2
,3
]}

Saeki, Norihisa ^{[5
]}

Sasaki, Hiroki ^{[5
]}

Grant, Struan F. A. ^{[1
,6
,7
]}

Iolascon, Achille ^{[8
,14
]}

Mosse, Yael P. ^{[2
,3
,6
]}

Cole, Kristina A. ^{[2
,3
,6
]}

Li, Hongzhe ^{[4
]}

Devoto, Marcella ^{[4
,6
,7
,9
]}

McGrady, Patrick W. ^{[10
,11
]}

London, Wendy B. ^{[12
,13
]}

Capasso, Mario ^{[8
,14
]}

Rahman, Nazneen ^{[15
]}

Hakonarson, Hakon ^{[1
,6
,7
]}

Maris, John M. ^{[2
,3
,6
]}

机构：

[1] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[3] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[4] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[5] Natl Canc Ctr, Res Inst, Div Genet, Tokyo 1040045, Japan

[6] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[7] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[8] CEINGE Biotecnol Avanzate, I-80145 Naples, Italy

[9] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy

[10] Univ Florida, Dept Stat, Gainesville, FL 32603 USA

[11] Childrens Oncol Grp, Gainesville, FL 32603 USA

[12] Dana Farber Childrens Hosp, Ctr Canc, Boston, MA 02115 USA

[13] Childrens Oncol Grp, Boston, MA 02115 USA

[14] Univ Naples Federico 2, Dept Biochem & Med Biotechnol, I-80131 Naples, Italy

[15] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England

来源：

NATURE | 2011年 / 469卷 / 7329期

基金：

美国国家卫生研究院;

关键词：

COPY NUMBER; CHROMOSOMAL TRANSLOCATIONS; ACTIVATING MUTATIONS; ALK KINASE; GENE; TRANSCRIPTION; CANCER; INTERACTS; TARGET; CELLS;

D O I：

10.1038/nature09609

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths(1,2). 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 x 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.

引用

页码：216 / 220

页数：5

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