Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.Development and application of statistical models for medical scientific researc

Validation Study of Existing Gene Expression Signatures for Anti-TNF Treatment in Patients with Rheumatoid Arthritis

So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response

Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization

PURPOSEWilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors.PATIENTS AND METHODSAll children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered.RESULTSA total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes (BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation.CONCLUSION(Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist

Accurate detection of low-level mosaic mutations in pediatric acute lymphoblastic leukemia using single molecule tagging and deep-sequencing

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Kennissynthese alcoholmarketing: Literatuuronderzoek naar de impact en het effect van alcoholmarketing op problematisch alcoholgebruik naar aanleiding van het Nationaal Preventieakkoord

Prompted by the National Prevention Agreement (2018), a systematic literature review and four focus group sessions were conducted to describe the current body of knowledge about the scope and consequences of alcohol marketing. We also identified several knowledge gaps and recommendations for future research. The most important conclusion is that the majority of scientific studies and reviews conclude that there are positive associations between alcohol marketing and alcohol consumption, also in (underage) youth. According to two recent and large review studies, this is a causal relationship. The possible effects of alcohol marketing for pregnant women, heavy drinkers, and addicted people is unknown. Furthermore, we conclude that alcohol marketing is omnipresent in Dutch society, and that alcohol marketing also reaches minors. Especially the presence of alcohol and alcohol marketing on social media is an issue of increasing concern. The possible effects of marketing for 0.0% drinks and the market penetration of these beverages in Dutch society are barely studied and require further attention

Dit programma bevat product placement: Effecten van sponsorvermeldingen in televisieprogramma's

Europese richtlijnen vereisen dat brand placement in televisieprogramma’s wordt kenbaar gemaakt door een tekst zoals "Dit programma bevat product placement" of door een PP (product placement) logo. Deze sponsorvermeldingen hebben als doel de televisiekijker te informeren over merken of producten die met commerciële doeleinden zijn opgenomen in televisieprogramma’s. Hebben deze vermeldingen het beoogde effect? En wat zijn de gevolgen voor de beoordeling van deze vorm van reclame en het merk? Met twee experimenten hebben we de effecten van sponsorvermeldingen op de verwerking en evaluatie van brand placement onderzocht. Deze studies tonen aan dat, als een sponsorvermelding wordt opgemerkt, deze de aandacht voor de brand placement vergroot en de kijker inderdaad bewuster maakt van het feit dat er reclame verwerkt zit in het programma. Deze herkenning van reclame leidt bovendien tot een betere merkherinnering, maar ook een kritischere evaluatie van de brand placement en minder positieve merkattitudes. Hiermee wordt aangetoond dat sponsorvermeldingen het door de wetgever beoogde doel kunnen bereiken, maar ook belangrijke gevolgen hebben voor de effectiviteit van de brand placement