Project description:Background: The current knowledge about the molecular mechanisms underlying the health benefits of exercise is still limited, especially in the pediatric population. We set out to investigate the effect of a 20-week exercise intervention on whole blood transcriptome profile (RNA-seq) in children with overweight/obesity. Methods: Twenty-four pre-pubertal children (10.21 ± 1.33 years, 46% girls) with overweight/obesity, were randomized to either a 20-week exercise program (intervention group; n=10), or to a non-exercise control group (usual lifestyle, n=14). Whole blood transcriptome profile was analysed using RNA-seq STRT2 technique. Gene expression analysis was carried out with the Limma R/Bioconductor software package, and the gene ontology (GO) and pathway enrichment analyses were performed using R. Ingenuity Pathway Analysis (IPA) was performed for gene network detection. The transcriptome data were in silico validated using PHENOPEDIA and meta-analysis database extrameta.org. Results: 161 genes were differentially expressed between the exercise and the control groups among boys, and 121 genes among girls (p-value < 0.05), while after multiple correction, no significant difference between groups persisted in gene expression profiles (FDR > 0.05). Based on non-corrected analyses, the enriched GO processes and molecular pathways highlighted the effect of exercise on different immune response related pathways in boys (antigen processing and presentation, infections, and T cell receptor complex) and girls (Fc epsilon RI signaling pathway) (FDR < 0.05). In silico data mining and validation analyses (using PHENOPEDIA and meta-analysis database extrameta.org) highlight top genes regulated by exercise such as CD6, HLA-C, TNFRSF1A, MYD88, and NFKBIA genes in boys and RAC1, ANXA6, FYN, INPP5D, PIK3CD and SPARC genes in girls. Conclusion: These results suggest that 20-week exercise program influences different immune processes in children with overweight/obesity. The transcriptome differences between boys and girls could partly be explained, in addition to the gender differences, by the distinct intensity in the exercise intervention as boys had stronger exercise stimulus in training. Our findings should be considered exploratory and preliminary given the relatively small sample size. Larger and more powered randomized controlled trials should confirm or contrast our findings.

Project description:Background: Normal cell BRCA1 epimutations have been associated with increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may have BRCA1 epimutations as their underlying cause is unknown. Neither are the time of occurrence and the potential inheritance patterns of BRCA1 epimutations established. Methods: To address these questions, we analyzed BRCA1 methylation status in breast cancer tissue and matched white blood cells (WBC) from 408 patients with 411 primary breast cancers, including 66 TNBCs, applying a highly sensitive sequencing assay, allowing allele-resolved methylation assessment. Further, to assess the time of origin and the characteristics of normal cell BRCA1 methylation, we analyzed umbilical cord blood of 1260 newborn girls and 200 newborn boys. Finally, we assessed BRCA1 methylation status among 575 mothers and 531 fathers of girls with (n = 102) and without (n = 473) BRCA1 methylation. Results: We found concordant tumor and mosaic WBC BRCA1 epimutations in 10 out of 66 patients with TNBC and in four out of six patients with estrogen receptor (ER)-low expression (<10%) tumors (combined: 14 out of 72; 19.4%; 95% CI 11.1–30.5). In contrast, we found concordance in only three out of 220 patients with 221 ER≥10% tumors and zero out of 114 patients with 116 HER2-positive tumors. Intraindividually, BRCA1 epimutations affected the same allele in normal and tumor cells. Assessing BRCA1 methylation in umbilical WBCs from girls, we found mosaic, predominantly monoallelic BRCA1 epimutations, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals, but no correlation to BRCA1 methylation status either in mothers or fathers. A significantly lower fraction of newborn boys carried BRCA1 methylation (9 / 200; 4.5%) as compared to girls (p = 0.038). Similarly, WBC BRCA1 methylation was found less common among fathers (16/531; 3.0%), as compared to mothers (46 / 575; 8.0%; p = 0.0003). Conclusions: Our findings suggest prenatal BRCA1 epimutations might be the underlying cause of around 20% of TNBC and low-ER expression breast cancers. Such constitutional mosaic BRCA1 methylation likely arise through gender-related mechanisms in utero, independent of Mendelian inheritance.

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Effects of 20-week exercise on whole-blood genome-wide DNA methylation profile in children with overweight/obesity

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