DNA methylation and breast cancer-associated variants

Ho, Peh Joo; Dorajoo, Rajkumar; Ivanković, Ivna; Ong, Simon Yew Kuang; Khng, Alexis Jiaying; Tan, Benita Kiat‐Tee; Tan, Veronique Kiak Mien; Lim, Swee Ho; Tan, Ern Yu; Tan, Su-Ming; Tan, Qing; Yan, Zhiyan; Ngeow, Joanne; Sim, Yirong; Chan, Peter; Chuan, Juliana Chen Jia; Chan, Ching Wan; Tang, Siau Wei; Hartman, Mikael; Li, Jingmei

doi:10.1007/s10549-021-06185-9

Cited by 9 publications

(15 citation statements)

References 41 publications

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“…We also assessed whether removal of recently described methylation quantitative loci (mQTLs) associated with breast cancer risk influenced the index. Ho et al 32 assessed 235 of the 313 breast cancer variants 31 with minor allele frequencies higher than 5% and based on this identified 822 cis-mQTLs of which 704 were present in our analysis set. Interestingly, 78 of these mQTLs were included in the WID-BC-index, which is more than expected by chance (observed to expected ratio 2.97 [95%CI 2.32–3.76, p < 0.001]); however removal of these 78 mQTLs from the WID-BC-index did not result in a significant drop in performance (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

et al. 2022

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Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

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Section: Resultsmentioning

confidence: 99%

“…mQTL data was obtained from the supplementary information of a recent publication by Ho et al 32 . The 822 probes at loci associated with breast cancer risk were extracted and those present in the WID-BC-index ( n = 78) were removed from the WID-BC-index for assessment of their influence on the performance.…”

Section: Methodsmentioning

confidence: 99%

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

et al. 2022

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“…Epigenetics, including DNA methylation, has been implicated in causing several diseases such as neuroblastoma [ 12 ], breast cancer [ 13 ], colon cancer [ 14 ], and liver cancer [ 14 ], via silencing tumor suppressor genes [ 15 ] and inducing oncogenes [ 12 ]. Recent studies have shown that the alternation of DNA methylation is a leading cause of colon cancer and being considered as biomarkers [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Almutairi

Alrefaei

et al. 2022

BioMed Research International

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Cigarette SMOKE (CS) considerably contributes to causing some diseases such as cancer, and it has a role in the alternation of gene expression through several mechanisms including epigenetics modification, particularly DNA methylation. EYA4 is one of the genes, that whose expression has been dysregulated in lung, colon, bladder, and breast cancer, leading to tumor progression. The alternation of DNA methylation levels has been implicated in regulating the expression of the EYA4 gene. Thus, in this study, we have shown the effect of CS on the DNA methylation level of the EYA4 promoter region as well as the methylation level on EYA4 expression. To determine the level of DNA methylation on the promoter region of the EYA4 gene, we have employed the bisulfite conversion treatment followed by the Sanger Sequence for 100 DNA samples taken from Saudi people (50 smokers and 50 nonsmokers). We found that 26% of DNA extracted from smoker samples is methylated, while there was no methylation identified in nonsmoker samples. Also, using the demethylating agents such as AZA on LoVo and Caco-2 cancer cell lines causes induction of transcription level of EYA4, implying the possible mechanism of DNA methylation in the upregulation of EYA4. These findings suggest the possible mechanism of CS in controlling the expression of EYA4 via changing the status of DNA methylation.

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“…However, DNA methylation is at least partially regulated by SNPs called mQTLs, which can be used as surrogates of a direct measure. The role of mQTLs in cancer development has already been identified for bladder, breast, colorectal and pancreatic cancers 32–34…”

Section: Discussionmentioning

confidence: 99%

“…The genetic component of methylation accounts for a small fraction of its variability; nevertheless, mQTLs could represent a good surrogate to study DNA methylation in epidemiological settings. Recently, several studies highlighted the association between mQTLs and risk of breast, bladder and prostate cancers 32–35. Heyn and colleagues conducted a small study on 49 PDAC cases and seven controls and identified rs401681, an mQTL in the TERT locus, to be associated with PDAC development 34.…”

Section: Introductionmentioning

confidence: 99%

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

et al. 2023

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IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate.Materials and methodsWe scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case–Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase.ResultsThe C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10−8in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of theRCCD1antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase ofRCCD1gene expression, made possible by the inactivity ofRCCD1-AS1.ConclusionWe identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

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DNA methylation and breast cancer-associated variants

Cited by 9 publications

References 41 publications

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

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