Background of the study.

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Breast cancer is a complex heterogeneous disease caused by the interactions of both intrinsic (genetic and non-genetic factors) and extrinsic (Age, gender, and family history) as the major factors (Cappetta et al, 2024). It is the main cause of cancer death and the most diagnosed cancer case in women in 140 of the world’s 184 countries (Tzenois et al 2024).

In a report in 2012 by the International Agency for Research on Cancer, it showed 1.7 million breast cancer new cases, and with 6.3 million new patients already diagnosed and reported in the previous 5 years (Tzenois et al 2024). Every year, an estimated 1.5 million women globally are diagnosed and confirmed with breast cancer, (Zahmatkesh et al 2017).

DNA methylation is a key process involved in the regulation of gene expression. DNA methylation is a molecular modification of DNA that is tightly associated with gene function and cell- type-specific gene function, it therefore provides an exquisite identity descriptor of a cell (Szyf, 2012). Interestingly, DNA methylation is potentially modifiable and is related to age and the strongest breast cancer risk predictor as a molecular biomarker for cancer (Horvath et al. 2012 & Capetta et al. 2024).

Several studies have investigated peripheral blood DNA methylation biomarkers in different cancer types including head and neck, breast, lung, bladder, gastric cancer, prostate, colorectal, and ovarian cancers (Langevin et al. 2012 & Sun et al. 2018).

Few studies have attempted to investigate the role of loci-specific DNA methylation in leukocytes as a marker of breast cancer, most of them by candidate gene approaches, and did not use a validation set to confirm their results (Guan et al. (Tang et al. 2016; 2019 & Capetta et al. 2024). However, there is no research reporting the uncovering DNA Methylation signatures in breast cancer using an in-silico approach. Hence, the need to delve into the study.

Hypothesis and critical questions.

DNA methylation states could serve as an important diagnostic tool in breast cancer care.
Therefore the pertinent questions to look into are;
How can DNA Methylation signature In breast cancer be uncovered using in-silico approach?
What are the changes in the breast cancer gene expressions that is impacted by DNA Methylation?
How can DNA Methylation be use as a molecular tool for diagnosing and early breast cancer detection?
It is also important to elucidate whether a set of specific gene methylation events would be sufficient in breast cancer diagnostics, or whether this would require more complex ‘signatures’ that involve coordinated changes in groups of genes. Hence, the need to uncover the DNA Methylation signatures in breast cancer using different datasets.

DNA methylation in humans.
DNA methylation, is a biological process that involves the addition of a methyl (CH3) group to a cytosine, most commonly at cytosine-guanine (CpG) sites, is a stable and ubiquitous epigenetic modification in humans (Peters et al., 2024).
DNA methylation pathways. A family of DNA methyltransferases (Dnmts) catalyzes the transfer of a methyl group from S-adenyl methionine (SAM) to the fifth carbon of cytosine residue to form 5-methylcytosine (5mC). (a) Dnmt3a and Dnmt3b are the de novo Dnmts and transfer methyl groups (red) onto naked DNA. (b) Dnmt1 is the maintenance Dnmt and maintains DNA methylation pattern during replication. When DNA undergoes semiconservative replication, the parental DNA stand retains the original DNA methylation pattern (gray). Dnmt1 associates at the replication foci and precisely replicates the original DNA methylation pattern by adding methyl groups (red) onto the newly formed daughter strand (blue), (Moore, 2012).