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Abstract Background Research on germline genetic variants relies on enough eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits, participants can contribute genetic samples conveniently from their home. Demographic and clinical factors were identified previously that influenced participation in mailed self-collection. People with pre-existing heritable diagnoses might participate differently in germline DNA collection which might render sampling biased in this group. In this nationwide cross-sectional study, we analysed predictive factors of participation in DNA self-collection including heritable diagnoses. Methods We identified childhood cancer survivors from the Swiss Childhood Cancer Registry for invitation to germline DNA self-sampling in September 2019. Participants received saliva sampling kits by postal mail at their home, were asked to fill them, sign an informed consent, and send them back by mail. Two reminders were sent to non-participants by mail. We compared demographic, clinical, and treatment information of participants with non-participants using univariable and multivariable logistic regression models. Results We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 19-37), of which 463 (50%) participated. After the initial send out of the sampling kit, 291 (63%) had participated, while reminder letters led to 172 additional participants (37%). Foreign nationality (odds ratio [OR] 0.5; 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5; CI 0.4-0.8), and survivors with a known cancer predisposition syndrome (OR 0.5; CI 0.3-1.0) were less likely to participate in germline DNA collection. Survivors with a second primary neoplasm (OR 1.9; CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3; CI 1.0-1.8) tended to participate more. Conclusions We showed that half of childhood cancer survivors participated in germline DNA self-sampling relying completely on mailing of sample kits. Written reminders increased the response by about one third. More targeted recruitment strategies may be advocated for people of foreign nationality, aged 30-39 years, and those with cancer predisposition syndromes. Perceptions of genetic research and potential barriers to participation of survivors need to be better understood. Trial registration Biobank: https://directory.bbmri-eric.eu/#/collection/bbmri-eric:ID:CH_HopitauxUniversitairesGeneve:collection:CH_BaHOP Research project : Clinicaltrials.gov: NCT04702321 .

Abstract Background 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. Methods 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. Results 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. Conclusions 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.