Heritable DNA methylation marks associated with susceptibility to breast cancer
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ABSTRACT:
PROVIDER: PRJNA414216 | ENA |
REPOSITORIES: ENA
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Project description:Genome-wide DNA Methylation analysis of 210 affected and unaffected individuals from 25 Australian families with multiple cases of breast cancer without carrying a mutation at breast cancer susceptibility genes. Genome-wide methylation was assessed using the Infinium HumanMethylation450K platform.
2017-10-14 | GSE104942 | GEO
Project description:Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
| S-EPMC5830448 | biostudies-literature
Project description:DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array. We used these families to systematically search the genome for methylation marks with Mendelian patterns of inheritance, then we tested the 1,000 most heritable marks for association with prostate cancer risk. After correcting for multiple testing, 41 heritable methylation marks were associated with prostate cancer risk. Separate analyses, based on 869 incident cases and 869 controls from a prospective cohort study, showed that 9 of these marks near the metastable epiallele VTRNA2-1 were also nominally associated with aggressive prostate cancer risk in the population.
| S-EPMC10275808 | biostudies-literature
Project description:Background: Pulmonary arterial hypertension (PAH) and breast cancer disproportionately affect women. Bone morphogenetic protein receptor type 2 (BMPR2) mutations, the most common genetic cause of heritable PAH, also exert tumor-suppressive functions, yet their role in linking these diseases remains unclear. Methods: We combined bioinformatic, epidemiologic, and experimental approaches. Public cancer datasets were mined for BMPR2 alterations. In vivo, mammary tumor development and pulmonary hemodynamics were assessed in female Bmpr2⁺/Δ71 rats with or without carcinogen (DMBA) exposure. Pulmonary arterial smooth-muscle cells (PASMCs) were exposed to tumor-conditioned media to test inflammatory proliferation. Finally, associations between breast cancer and PAH were examined in the French National Healthcare Database (>9,000 PAH patients). Results: BMPR2 expression was markedly reduced in human breast tumors, with recurrent somatic variants and deep deletions identified. Bmpr2⁺/Δ71 rats exhibited spontaneous mammary tumors and, following DMBA exposure, developed exacerbated pulmonary hypertension with increased vascular remodeling and inflammation. Tumor-bearing Bmpr2⁺/Δ71 rats showed elevated lung IL-1β and NF-κB activation. In vitro, conditioned media from Bmpr2⁺/Δ71 tumors induced proliferation of Bmpr2⁺/Δ71 PASMCs via IL-1β-dependent signaling, while neutralization of IL-1β attenuated this effect. Human PASMCs carrying BMPR2 mutations similarly displayed heightened IL-1β-induced proliferation. Epidemiologically, breast cancer incidence was more than doubled in patients with PAH compared with the general population, and PAH incidence was increased nearly nine-fold among patients with breast cancer, indicating a bidirectional relationship. Conclusions: These findings identify a reciprocal association between breast cancer and PAH mediated by defective BMPR2 signaling and tumor-associated inflammation. Breast cancer may act as a “second hit” unmasking BMPR2-related susceptibility to PAH, underscoring BMPR2 as a shared molecular vulnerability with implications for surveillance of at-risk populations.
2026-02-25 | GSE314019 | GEO
Project description:Incomplete reprogramming of organ-specific epigenetic marks during plant asexual reproduction leads to heritable phenotypic variation
| PRJEB26932 | ENA
Project description:<p>Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer such as BRCA1 and BRCA2 account for less than 25% of familial cases of breast cancer. Heritable epigenetic modifications, in the form of hypermethylated MLH1 promoter alleles, have recently been shown to promote hereditary nonpolyposis colorectal cancer. We investigated the potential for an epigenetic basis for hereditary breast cancer by performing deep bisulfite sequencing of CpG islands and known promoter regions in germline DNA from 100 familial or early-onset breast or ovarian cancer patients.</p>
| phs001699 | dbGaP
Project description:Characterizing Genetic Susceptibility to Breast and Prostate Cancer - BPC3
| PRJNA263216 | ENA
Project description:Genome-wide dynamic changes in DNA methylation are indispensable for germline development and genomic imprinting in mammals. Here, we report single-base resolution DNA methylome and transcriptome maps of mouse germ cells, generated using whole-genome shotgun bisulfite sequencing and cDNA sequencing (mRNA-seq). Oocyte genomes showed a significant positive correlation between mRNA transcript levels and methylation of the transcribed region. Sperm genomes had nearly complete coverage of methylation, except in the CpG-rich regions, and showed a significant negative correlation between gene expression and promoter methylation. Thus, these methylome maps revealed that oocytes and sperms are widely different in the extent and distribution of DNA methylation. Furthermore, a comparison of oocyte and sperm methylomes identified more than 1,600 CpG islands differentially methylated in oocytes and sperm (germline differentially methylated regions, gDMRs), in addition to the known imprinting control regions (ICRs). About half of these differentially methylated DNA sequences appear to be at least partially resistant to the global DNA demethylation that occurs during preimplantation development. In the absence of Dnmt3L, neither methylation of most oocyte-methylated gDMRs nor intragenic methylation was observed. There was also genome-wide hypomethylation, and partial methylation at particular retrotransposons, while maintaining global gene expression, in oocytes. Along with the identification of the many Dnmt3L-dependent gDMRs at intragenic regions, the present results suggest that oocyte methylation can be divided into 2 types: Dnmt3L-dependent methylation, which is required for maternal methylation imprinting, and Dnmt3L-independent methylation, which might be essential for endogenous retroviral DNA silencing. The present data provide entirely new perspectives on the evaluation of epigenetic markers in germline cells.
| S-EPMC3252278 | biostudies-literature
Project description:We aimed to explore the effect of the breast cancer susceptibility gene TOX3 on estrogen synthesis from the perspective of estrogen production, in an attempt to link abnormalities in hormone production with the development of breast cancer. After overexpression of TOX3, several crucial key genes and pathways that contribute to estrogen production were upregulated. Forced expression of TOX3 also promotes proliferation and inhibits apoptosis of granulosa cells. These findings discuss the possible impact of susceptibility genes and steroid hormones on breast cancer from the perspective of extra-mammary tissues such as those in the ovary, thus providing new insights for early prevention and treatment of breast cancer.
2021-02-04 | GSE161341 | GEO
Project description:Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are unknown. Here, we perform metabolic methyl-labelling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans. We find that methylation is transmitted to descendants in proteins, RNA, DNA and lipids. We further find that in response to parental starvation, naïve progeny display reduced fertility, increased heat stress resistance, and extended longevity. This intergenerational hormesis is accompanied by a heritable increase in N6’-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1 as the m6,2A methyltransferase in C. elegans and find that dimt-1 is required for the intergenerational hormesis phenotypes. Together this study provides the first labeling and tracking of heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating the heritable response to starvation
2022-05-01 | GSE175363 | GEO