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Nature:利用GWAS方法识别致癌基因

来源:Nature 中文 2011-01-13 20:46

全基因组关联研究(GWAS)表明,在LMO1位点内的单核苷酸变异体与“成神经细胞瘤”(一种儿童期交感神经系统癌症)的遗传性易感性相关。LMO1编码一种以前与癌症联系在一起的转录调控因子。同一位点上的获得性结构变异在“成神经细胞瘤”患者中普遍存在,说明通过GWAS方式识别出的位点也许容易受体细胞改变(somatic alteration)的影响,所以可以用来识别潜在治疗目标和/或癌症攻击性的生物标记。(生物谷 Bioon.com)

生物谷推荐原文出处:

Nature  doi:10.1038/nature09609

Integrative genomics identifies LMO1 as a neuroblastoma oncogene

Kai Wang,Sharon J. Diskin,Haitao Zhang,Edward F. Attiyeh,Cynthia Winter,Cuiping Hou,Robert W. Schnepp,Maura Diamond,Kristopher Bosse,Patrick A. Mayes,Joseph Glessner,Cecilia Kim,Edward Frackelton,Maria Garris,Qun Wang,Wendy Glaberson,Rosetta Chiavacci,Le Nguyen,Jayanti Jagannathan,Norihisa Saeki,Hiroki Sasaki,Struan F. A. Grant,Achille Iolascon,Yael P. Mosse,Kristina A. Cole,

Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths1, 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?×?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.

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