Comparative expression analysis of BRCA1mosMe fibroblast vs. BRCA1wt fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Anna Etzold
PROVIDER: E-GEOD-71078 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We performed a comprehensive molecular and cellular analysis of primary dermal fibroblasts taken from a patient with recurrent cancers, harboring a BRCA1 mosaic epimutation (BRCA1mosMe) in comparison to their isogenic control fibroblasts (BRCA1wt), taken from the patient´s healthy monozygous sister.
2015-12-31 | GSE71078 | GEO
Project description:Normal breast fibroblasts, breast cancer associated fibroblasts, fibroblasts taken at least 2cm from cancer margins and femur-derived human mesenchymal stem cells were profiled for comparative purposes Ex vivo cultured primary cells of different anatomical origin were expression profiled under low serum conditions: cancer-associated fibroblasts, fibroblasts from a distance of at least 2cm from the cancers' edge, fibroblasts from cancer-free breasts and mesenchymal stromal cells from the marrow of femurs. Biological Replicates= 46. Technical Replicates= 17
2011-10-24 | E-GEOD-29270 | biostudies-arrayexpress
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.
2023-10-26 | GSE243956 | GEO
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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Project description:Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation. Five members of a three-generation Caucasian Lynch syndrome family with an autosomal dominant MLH1 epimutation linked to a single nucleotide variant (c.-27C>A) within the MLH1 5'UTR were examined for copy number variations and retention of heterozygosity on chromosome 3. These five carriers of constitutional MLH1 methylation and the c.-27C>A variant were compared with 300 healthy Caucasian controls from the Wellcome Trust Case Control Consortium using three algorithms (QuantiSNP, PennCNV, COKGEN) to detect any copy number variants. The five family members studied were female (the proband II5, her affected mother I1, and three asymptomatic relatives II2, II4 and III2) are labeled according to the pedigree in Figure 3 of the associated publication (Hitchins et al., Cancer Cell, 2011). The supplementary file 'GSE30348_gw6.lrr_baf.txt' contains log R ratio and B-allele frequency values in a tab-delimited format with one marker per row.
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Project description:The in-vitro analysis of the hypomethylation of the imprinting control region 1 (ICR1) within the IGF2/H19 locus is challenged by the mosaic distribution of the epimutation in tissues from children with Silver-Russell syndrome (SRS). For excluding mosaicism, clonal cultures of skin fibroblasts from four children with SRS and three controls were analyzed. Cell proliferation, IGF-II secretion, and expression of IGF2 and H19 were measured. Microarray expression analysis was performed. Single cell expansion established severely ICR1 hypomethylated clones (SRShypo) and normomethylated clones (SRSnormo) from patients and controls (Cnormo). IGF2 expression was below the detection limit of the qRT-PCR assay, while H19 expression was detectable, without differences between fibroblast clones. Cell count-related IGF-II release was comparable in supernatants of SRShypo and Cnormo. Cell proliferation was diminished in SRShypo compared to Cnormo (p=.035). Microarray analysis revealed gene expression changes in SRS clones predicting a decrease of cell proliferation and a delay of mitosis. The analysis of severely ICR1 hypomethylated clonal fibroblasts did not reveal any functional differences towards the normomethylated clones with respect to IGF2 and H19 expression. Furthermore, a clear difference to the clones from healthy individuals was not detected except from a lower proliferation rate arisen from impaired cell cycle progression.
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