全基因組關(guān)聯(lián)研究(GWAS)表明,，在LMO1位點(diǎn)內(nèi)的單核苷酸變異體與“成神經(jīng)細(xì)胞瘤”（一種兒童期交感神經(jīng)系統(tǒng)癌癥）的遺傳性易感性相關(guān)。LMO1編碼一種以前與癌癥聯(lián)系在一起的轉(zhuǎn)錄調(diào)控因子,。同一位點(diǎn)上的獲得性結(jié)構(gòu)變異在“成神經(jīng)細(xì)胞瘤”患者中普遍存在,，說(shuō)明通過GWAS方式識(shí)別出的位點(diǎn)也許容易受體細(xì)胞改變(somatic alteration)的影響，所以可以用來(lái)識(shí)別潛在治療目標(biāo)和/或癌癥攻擊性的生物標(biāo)記,。（生物谷 Bioon.com）
生物谷推薦原文出處：
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.
