Rare Variants in TP53 and Susceptibility to Neuroblastoma

Diskin, Sharon J.; Capasso, Mario; Diamond, Maura; Oldridge, Derek A.; Conkrite, Karina L.; Bosse, Kristopher R.; Russell, Mike R.; Iolascon, Achille; Hákonarson, Hákon; Devoto, Marcella; Maris, John M.

doi:10.1093/jnci/dju047

Cited by 107 publications

(90 citation statements)

References 25 publications

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“…We have already demonstrated by using genome-wide association studies that common variants are associated with risk of neuroblastoma [4-7]. We thus speculated that also rare germline variants could have a role in the etiology of this pediatric malignancy.…”

Section: Discussionmentioning

confidence: 97%

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

et al. 2016

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The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

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Section: Discussionmentioning

confidence: 97%

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

et al. 2016

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“…A neuroblastoma GWAS has identified multiple disease susceptibility loci 2,7-13 , with the signal within the LIM domain only 1 ( LMO1 ) locus at 11p15 2 , a transcriptional co-regulator containing two zinc finger LIM domains that nucleate and regulate transcription factor complexes 14 , being most robust. The main members of the LMO gene family, LMO1-4 , are all implicated in cancer including LMO1 and LMO2 translocations in T-cell leukemia 15,16 , and we previously provided the first evidence that LMO1 was a bona fide neuroblastoma oncogene 2 .…”

mentioning

confidence: 99%

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism

Oldridge

Wood

Weichert-Leahey

et al. 2015

Nature

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Summary Neuroblastoma is a pediatric malignancy that typically arises in early childhood and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumors with excellent outcomes to widely metastatic disease where long-term survival is approximately 40% despite intensive therapy1. A previous genome-wide association study (GWAS) identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumor cells2. Here we sought to discover the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding sites. SNP rs2168101 G>T was the most highly associated variant (combined P=7.47×10-29, Odds Ratio 0.65, 95% CI: 0.60-0.70) and resided in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 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. We show 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<0.0001). We demonstrate allelic imbalance favoring the G-containing strand in tumors heterozygous for this SNP as demonstrated both by RNA sequencing (P<0.0001) and reporter assays (P=0.002). These findings show that a recently evolved polymorphism within a super-enhancer 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.

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“…In particular, consistent with a putative effect of the variant T-allele on weakening the mRNA secondary structure, we did show that miR-204 is able, by means of a still undisclosed mechanism, to decrease the stability of the PHOX2B mRNA, at a larger extent in the presence of the T allele than in the presence of the A allele. This suggests a putative role of SNP rs1063611 as susceptibility locus for neuroblastoma, thus making highly probable an association between this SNP and neuroblastoma which might deserve to be tested in a large case-control study [38,39]. Our result also suggests a genotype-dependent effect of miR-204 which should be therefore considered when reasoning about possible therapeutic interventions and personalized medicine.…”

Section: Accepted Manuscriptmentioning

confidence: 57%

miR-204 mediates post-transcriptional down-regulation of PHOX2B gene expression in neuroblastoma cells

Bachetti¹,

Zanni²,

Ravazzolo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Rare Variants in TP53 and Susceptibility to Neuroblastoma

Cited by 107 publications

References 25 publications

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism

miR-204 mediates post-transcriptional down-regulation of PHOX2B gene expression in neuroblastoma cells

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