Integrative genomics identifies LMO1 as a neuroblastoma oncogene

Abstract

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.

The LMO2 oncogene regulates DNA replication in hematopoietic cells

“…Two other LIM-only proteins, LMO1 and LMO4, are also important determinants of cell cycle progression in neuroblastoma (23) and in breast cancer associated with genomic instability (22), respectively, suggesting that the mechanism(s) described here may be extended to these proteins. Emerging evidence indicates that oncogenes, such as c-MYC or HOXD13, can be part of nontranscriptional complexes involved in DNA replication (54,57).…”

“…As a consequence, LMO2 is misexpressed in the T lineage, where it is normally absent. In addition, LMO proteins are frequently deregulated in breast cancers (22) and neuroblastomas (23), pointing to their importance in cell transformation. In particular, in patients who eventually developed T-ALL associated with LMO2 activation after gene therapy, T-cell hyperproliferation was observed early during the preleukemic stage (19).…”

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

“…Through a genomewide association study (GWAS) of sporadic neuroblastoma, we have reported common single nucleotide polymorphisms (SNPs) associated with neuroblastoma susceptibility at CASC15 4, BARD1 5, LMO1 6, DUSP12 7, HSD17B12 7, DDX4/IL31RA 7, HACE1 8 and LIN28B 8 loci. Importantly, many of these GWAS‐identified genes have been shown to be key factors in both initiating and sustaining tumorigenesis 6, 8, 9, 10, 11. These results suggest that neuroblastoma tumorigenesis could be the result of multiple genetic alterations and that these variants can also influence the clinical outcome of disease.…”

Overview and recent advances in the treatment of neuroblastoma

“…Genome-wide association studies (GWAS) have also identified additional germline genetic variants in neuroblastoma patients, including single-nucleotide polymorphisms in LIN28B, BARD1, and LMO1, among others [26][27][28][29] as well as other polymorphisms in other chromosomal regions yet to be fully characterized [30,31]. These polymorphisms occur relatively frequently in the general population and may contribute to the development of sporadic neuroblastoma, although the functional roles of these germline variants and other somatic alterations remain to be elucidated.…”