Nguyen-Dumont T.,Genetic Cancer Susceptibility Group |
Jordheim L.P.,University of Lyon |
Michelon J.,Genetic Cancer Susceptibility Group |
Forey N.,Genetic Cancer Susceptibility Group |
And 7 more authors.
BMC Medical Genomics | Year: 2011
Background: The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods. We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment. Results: We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions: Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms. © 2011 Nguyen-Dumont et al; licensee BioMed Central Ltd. Source
Hernandez-Vargas H.,International Agency for Research on Cancer IARC |
Castelino J.,University of Leeds |
Silver M.J.,MRC International Nutrition Group |
Silver M.J.,University of Cambridge |
And 16 more authors.
International Journal of Epidemiology | Year: 2015
Background: Exposure to environmental toxins during embryonic development may lead to epigenetic changes that influence disease risk in later life. Aflatoxin is a contaminant of staple foods in sub-Saharan Africa, is a known human liver carcinogen and has been associated with stunting in infants. Methods: We have measured aflatoxin exposure in 115 pregnant women in The Gambia and examined the DNA methylation status of white blood cells from their infants at 2-8 months old (mean 3.6±0.9). Aflatoxin exposure in women was assessed using an ELISA method to measure aflatoxin albumin (AF-alb) adducts in plasma taken at 1-16 weeks of pregnancy. Genome-wide DNA methylation of infant white blood cells was measured using the Illumina Infinium HumanMethylation450beadchip. Results: AF-alb levels ranged from 3.9 to 458.4 pg/mg albumin. We found that aflatoxin exposure in the motherswas associated to DNAmethylation in their infants for 71 CpG sites (false discovery rate<0.05), with an average effect size of 1.7% change in methylation. Aflatoxin-associated differential methylationwas observed in growth factor genes such as FGF12 and IGF1, and immune-related genes such as CCL28, TLR2 and TGFBI. Moreover, one aflatoxin-associated methylation region (corresponding to themiR-4520b locus)was identified. Conclusions: This study shows that maternal exposure to aflatoxin during the early stages of pregnancy is associated with differential DNA methylation patterns of infants, including in genes related to growth and immune function. This reinforces the need for interventions to reduce aflatoxin exposure, especially during critical periods of fetal and infant development. © The Author 2015. Source