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Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk : Data From 228 951 Women of European Descent

Yang, Yaohua ; Wu, Lang ; Shu, Xiao Ou ; Cai, Qiuyin ; Shu, Xiang ; Li, Bingshan ; Guo, Xingyi ; Ye, Fei ; Michailidou, Kyriaki and Bolla, Manjeet K. , et al. (2020) In Journal of the National Cancer Institute 112(3). p.295-304
Abstract

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study... (More)

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

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@article{46bbca7f-14af-457a-9fea-83c1d375c6c6,
  abstract     = {{<p>BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.</p>}},
  author       = {{Yang, Yaohua and Wu, Lang and Shu, Xiao Ou and Cai, Qiuyin and Shu, Xiang and Li, Bingshan and Guo, Xingyi and Ye, Fei and Michailidou, Kyriaki and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Andrulis, Irene L. and Brenner, Hermann and Chenevix-Trench, Georgia and Campa, Daniele and Castelao, Jose E. and Gago-Dominguez, Manuela and Dörk, Thilo and Hollestelle, Antoinette and Lophatananon, Artitaya and Muir, Kenneth and Neuhausen, Susan L. and Olsson, Håkan and Sandler, Dale P. and Simard, Jacques and Kraft, Peter and Pharoah, Paul D.P. and Easton, Douglas F. and Zheng, Wei and Long, Jirong}},
  issn         = {{1460-2105}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{295--304}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of the National Cancer Institute}},
  title        = {{Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk : Data From 228 951 Women of European Descent}},
  url          = {{http://dx.doi.org/10.1093/jnci/djz109}},
  doi          = {{10.1093/jnci/djz109}},
  volume       = {{112}},
  year         = {{2020}},
}