Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.

Perfluoroalkyl substances (PFAS) are widespread synthetic substances with various adverse health effects. A potential mechanism of toxicity for PFAS is via epigenetic changes, such as DNA methylation. However, few studies have evaluated associations between PFAS exposure and DNA methylation among adults, and data is especially scarce for women. Furthermore, exposure to environmental pollutants has been associated with epigenetic age acceleration, but no studies have yet evaluated whether PFAS is associated with epigenetic age acceleration. To investigate whether exposure to PFAS is associated with alteration of DNA methylation and epigenetic age acceleration among women. In this observational pilot study, 59 women (aged 20-47 years at enrollment in 2014) from Ronneby, Sweden, an area with historically high PFAS exposure due to local drinking water contamination, were divided into three PFAS exposure groups (low, medium, and high). Genome-wide methylation of whole-blood DNA was analyzed using the Infinium MethylationEPIC BeadChip. Ingenuity Pathway Analysis was used for in silico functional assessment. Epigenetic age acceleration was derived from the DNA methylation data using Horvath's epigenetic skin and blood clock. 117 differentially methylated positions (q < 0.017) and one near-significantly differentially methylated region (S100A13, FWER = 0.020) were identified. In silico functional analyses suggested that genes with altered DNA methylation (q < 0.05) were annotated to cancer, endocrine system disorders, reproductive system disease, as well as pathways such as estrogen receptor signaling, cardiac hypertrophy signaling, PPARα/RXRα activation and telomerase signaling. No differences in epigenetic age acceleration between PFAS exposure groups were noted (p = 0.43). The data suggests that PFAS exposure alters DNA methylation in women highly exposed to PFAS from drinking water. The observed associations should be verified in larger cohorts, and it should also be further investigated whether these changes in methylation also underlie potential phenotypic changes and/or adverse health effects of PFAS.

Neuroblastoma is the most common extracranial solid tumor in children. This cancer has a low frequency of TP53 mutations and its downstream pathway is usually intact. This study assessed the efficacy of the p53 activator, PRIMA-1MET, in inducing neuroblastoma cell death. CellTiter 2.0 was used to study susceptibility and specificity of NB cell lines to PRIMA-1MET. Real-time PCR and western blot were used to assess the most common p53 transactivation targets. Induction of p53 and Noxa, and inhibition of Cas3/7, were used to assess impact on cell death after PRIMA-1MET treatment. Flow cytometry was used to analyze cell cycle phase and induction of apoptosis, reactive oxygen species, and the collapse of mitochondrial membrane potential. Neuroblastoma cell lines were at least four times more susceptible to PRIMA-1MET than were primary fibroblasts and keratinocyte cell lines. PRIMA-1MET induced cell death rapidly and in all cell cycle phases. Although PRIMA-1MET activated p53 transactivation activity, p53’s role is likely limited because its main targets remained unaffected, whereas pan-caspase inhibitor demonstrated no ability to prevent cell death. PRIMA-1MET induced oxidative stress and modulated the methionine/cysteine/glutathione axis. Variations of MYCN and p53 modulated intracellular levels of GSH and resulted in increased/decreased sensitivity of PRIMA-1MET. PRIMA-1MET inhibited thioredoxin reductase, but the effect of PRIMA-1MET was not altered by thioredoxin inhibition. PRIMA-1MET could be a promising new agent to treat neuroblastoma because it demonstrated good anti-tumor action. Although p53 is involved in PRIMA-1MET-mediated cell death, our results suggest that direct interaction with p53 has a limited role in neuroblastoma but rather acts through modulation of GSH levels.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts.

Background: Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combiningin vitroinformation with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls.Methods: First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic.Results: After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as “Cell growth and death”, “Signalling molecules and interaction”, “Cancer”, and “Infectious disease”.Conclusions: This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising.Trial registration: For the clinical dataset: Clinicaltrials.gov:NCT01257854.https://clinicaltrials.gov/ct2/history/NCT01257854.