Abstract: Background Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. Methods Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case-control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. Results We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. Conclusion N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well

Alcohol consumption is a well established risk factor for upper aerodigestive tract cancer (UADTC). However, detailed knowledge on whether risk varies with respect to drinking pattern, beverage type and drinking cessation remains unclear. Two data sources were used to investigate pattern and cessation of alcohol consumption in relation to risk of UADTC: the Alcohoi-Related Cancers and Genetic Susceptibility in Europe (ARCAGE) case-control study of UADTC (2,304 cases/2,227 controls) and the International Head and Neck cancer Epidemiology (INHANCE) Consortium of pooled individual-level data from 19 case-control studies (13,269 cases/18,261 controls). -- We observed strong dose-response relationships with alcohol drinking, a finding observed overall and among never smokers in whom confounding by smoking could not have contributed. The UADTC risk was similarly elevated with wine, beer or liquor consumption. Drinking patterns affected UADTC, with risks particularly raised among drinkers who binged, drank before noon or between meals. Effects were consistent for younger, middle aged and older populations. However, middle aged subjects had higher population attributable fractions for alcohol consumption (49%) compared to younger (30%) and older (35%) subjects due to higher numbers of drinkers and higher drinking levels. Drinking cessation showed a beneficial effect after approximately 20 years, whereas the risk reduction after quitting smoking was within as little as one to four years. For cessation of both, drinking and smoking, risk was reduced to the level of never users after 20 years of quitting these habits. -- Alcohol drinking is a risk factor for UADTC at all ages and in both smokers and never smokers. Consumption of wine, beer and liquor has similar carcinogenic effects on UADTC risk.