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© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Seit 1970 richten wir an der Univ.-Hautklinik Gottingen unser Augenmerk bewust in zunehmendem Mase auf die psychosozialen und psychosomatischen Zusammenhange bei der Entstehung und im Verlauf von Hautkrankheiten. Die zunachst vornehmlich aus der wissenschaftlichen und poliklinischen Erfahrung des Dermatologen resultierende Beschaftigung fundierten wir seit 1973 durch die standige Zusammenarbeit mit einem voll in die Klinik integrierten Psychologen und ubertrugen sie auch auf den stationaren Bereich.

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A genome-wide association study (GWAS) has shown that single nucleotide variants within the LMO1 locus are associated with inherited susceptibility to neuroblastoma, a childhood cancer of the sympathetic nervous system. LMO1 encodes a transcriptional regulator previously linked to cancers. Acquired structural variation in the same locus is common in patients with neuroblastoma, suggesting that loci identified through GWAS approaches might also be prone to somatic alterations that influence tumour progression. Such studies could help to identify potential therapy targets and/or biomarkers of cancer aggressiveness. Here, single nucleotide variants within the LMO1 locus are shown to be associated with inherited susceptibility to neuroblastoma, a childhood cancer of the sympathetic nervous system. Acquired structural variation in the same locus was also frequently found in neuroblastoma patients, leading to the suggestion that loci identified through genome-wide association studies might be also prone to somatic alterations and therefore identify potential therapy targets and/or biomarkers of tumour aggressiveness. 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