Neuroblastoma, Susceptibility To, 7

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2019-09-22
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For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).

Mapping

To identify genetic risk factors for neuroblastoma, Wang et al. (2011) performed a genomewide association study on 2,251 patients and 6,097 control subjects of European ancestry from 4 case series. Wang et al. (2011) reported a significant association with LMO1 (186921) at 11p15.4 (rs110419, combined p = 5.2 x 10(-16), odds ratio (OR) risk allele = 1.34, 95% CI 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 paralogs LMO2 (180385), LMO3 (180386), and LMO4 (603129) have each been implicated in cancer. In parallel, Wang et al. (2011) analyzed genomewide DNA copy number alterations in 701 primary tumors and 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 less than 0.0001) and survival (p = 0.041). The germline SNP risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumors, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA-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. Wang et al. (2011) concluded that their studies showed 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.

Molecular Genetics

Oldridge et al. (2015) investigated the causal DNA variant at the LMO1 locus and the mechanism by which it leads to neuroblastoma tumorigenesis. The authors first imputed all possible genotypes across the LMO1 locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor-binding sites. The authors showed that SNP rs2168101G-T (186921.0001) is the most highly associated variant (combined p = 7.47 x 10(-29), OR 0.65, 95% CI 0.60-0.70), and resides in a superenhancer defined by extensive acetylation of histone H3 lysine-27 (H3K27) within the first intron of LMO1. The ancestral G allele that is associated with tumor formation resides in a conserved GATA transcription factor-binding motif. Oldridge et al. (2015) showed that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (p = 0.028) in neuroblastoma primary tumors, and ablates GATA3 binding (p less than 0.0001). Oldridge et al. (2015) demonstrated allelic imbalance favoring the G-containing strand in tumors heterozygous for this SNP, as demonstrated both by RNA sequencing and reporter assays. The authors concluded that their findings indicated that a recently evolved polymorphism within a superenhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumor cells.