Epigenetic modifications of DNA repair genes in breast cancer

Every day the cell is exposed to internal and external stress which can lead to genome instability. Over the years of evolution, the cell developed the DNA damage response (DDR). Genetic and epigenetic changes of genes involved in the DDR can increase the risk of developing cancer. By linking together DNA methylation and RNA sequencing data derived from The Cancer Genome Atlas (TCGA), EYA2 and DMC1 were identified as candidates of gene silencing by CpG promoter methylation in breast cancer. Primary breast cancer tissue samples, normal breast tissue samples and cell lines were pyrosequenced to validate aberrant promoter methylation in breast cancer patients. After establishing model cell lines, mRNA expression levels were measured in cell lines and breast tissue samples to confirm gene silencing by promoter methylation. Both EYA2 and DMC1 are found aberrantly promoter methylated in primary breast tumour samples compared to normal breast tissue. EYA2 mRNA expression is reduced in cancer cell lines with aberrant EYA2 promoter methylation. However, aberrant EYA2 promoter methylation does not associate with impact on survival. There is a strong indication of a negative correlation in our sample set, between DMC1 promoter methylation and DMC1 mRNA expression. Survival analyses indicate that aberrant DMC1 promoter methylation could impact breast cancer-specific survival. QPCR results indicate that DMC1 (m)RNA is expressed in normal breast tissue samples and breast tissue cell lines (normal and cancer). To our knowledge, this study shows for the first time that DMC1 is expressed in somatic cells, without being under extreme conditions of stress.The Icelandic Centre for Research: grant IDs #14193-051 and #152077-05