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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 deaths. 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?

SUBMITTER: Wang K

PROVIDER: S-EPMC3320515 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Integrative genomics identifies LMO1 as a neuroblastoma oncogene.

Wang Kai K Diskin Sharon J SJ Zhang Haitao H Attiyeh Edward F EF Winter Cynthia C Hou Cuiping C Schnepp Robert W RW Diamond Maura M Bosse Kristopher K Mayes Patrick A PA Glessner Joseph J Kim Cecilia C Frackelton Edward E Garris Maria M Wang Qun Q Glaberson Wendy W Chiavacci Rosetta R Nguyen Le L Jagannathan Jayanti J Saeki Norihisa N Sasaki Hiroki H Grant Struan F A SF Iolascon Achille A Mosse Yael P YP Cole Kristina A KA Li Hongzhe H Devoto Marcella M McGrady Patrick W PW London Wendy B WB Capasso Mario M Rahman Nazneen N Hakonarson Hakon H Maris John M JM

Nature 20101201 7329

Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. 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% confi ...[more]

PMID: 21124317

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Project description:BackgroundDespite the extensive research approaches applied to characterise malignant melanoma, no specific molecular markers are available that are clearly related to the progression of this disease. In this study, our aims were to define a gene expression signature associated with the clinical outcome of melanoma patients and to provide an integrative interpretation of the gene expression -, copy number alterations -, and promoter methylation patterns that contribute to clinically relevant molecular functional alterations.MethodsGene expression profiles were determined using the Affymetrix U133 Plus2.0 array. The NimbleGen Human CGH Whole-Genome Tiling array was used to define CNAs, and the Illumina GoldenGate Methylation platform was applied to characterise the methylation patterns of overlapping genes.ResultsWE IDENTIFIED TWO SUBCLASSES OF PRIMARY MELANOMA: one representing patients with better prognoses and the other being characteristic of patients with unfavourable outcomes. We assigned 1,080 genes as being significantly correlated with ulceration, 987 genes were downregulated and significantly enriched in the p53, Nf-kappaB, and WNT/beta-catenin pathways. Through integrated genome analysis, we defined 150 downregulated genes whose expression correlated with copy number losses in ulcerated samples. These genes were significantly enriched on chromosome 6q and 10q, which contained a total of 36 genes. Ten of these genes were downregulated and involved in cell-cell and cell-matrix adhesion or apoptosis. The expression and methylation patterns of additional genes exhibited an inverse correlation, suggesting that transcriptional silencing of these genes is driven by epigenetic events.ConclusionUsing an integrative genomic approach, we were able to identify functionally relevant molecular hotspots characterised by copy number losses and promoter hypermethylation in distinct molecular subtypes of melanoma that contribute to specific transcriptomic silencing and might indicate a poor clinical outcome of melanoma.

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Integrative genomics identifies LMO1 as a neuroblastoma oncogene.

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Integrative genomics identifies LMO1 as a neuroblastoma oncogene.

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