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Title: DNA methylation and breast cancer-associated variants
Authors: Ho, Peh Joo
Dorajoo, Rajkumar 
Ivankovic, Ivna
Ong, Seeu Si
Khng, Alexis Jiaying
Tan, Benita Kiat-Tee 
Tan, Veronique Kiak Mien 
Lim, Swee Ho 
Tan, Ern Yu
Tan, Su-Ming 
Tan, Qing Ting 
Yan, Zhiyan 
Ngeow, Joanne
Sim, Yirong 
Chan, Patrick 
Chuan, Juliana Chen Jia 
Chan, Ching Wan 
Tang, Siau Wei 
Hartman, Mikael 
Li, Jingmei 
Keywords: Science & Technology
Life Sciences & Biomedicine
DNA methylation
Breast cancer
Polygenic risk score
Genome-wide association study
Issue Date: 26-Mar-2021
Publisher: SPRINGER
Citation: Ho, Peh Joo, Dorajoo, Rajkumar, Ivankovic, Ivna, Ong, Seeu Si, Khng, Alexis Jiaying, Tan, Benita Kiat-Tee, Tan, Veronique Kiak Mien, Lim, Swee Ho, Tan, Ern Yu, Tan, Su-Ming, Tan, Qing Ting, Yan, Zhiyan, Ngeow, Joanne, Sim, Yirong, Chan, Patrick, Chuan, Juliana Chen Jia, Chan, Ching Wan, Tang, Siau Wei, Hartman, Mikael, Li, Jingmei (2021-03-26). DNA methylation and breast cancer-associated variants. BREAST CANCER RESEARCH AND TREATMENT 188 (3) : 713-727. ScholarBank@NUS Repository.
Abstract: Background: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants. Methods: Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium. Results: Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time. Conclusions: Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.
ISSN: 01676806
DOI: 10.1007/s10549-021-06185-9
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