Abstract
Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.
Highlights
Breast cancer is a complex and heterogeneous disease caused by the interactions of both genetic and non-genetic factors
Blood DNA methylation profiling reveals a panel of differentially methylated CpGs that discriminates sporadic breast cancer patients and healthy controls
To identify differentially methylated CpG sites (CpGDMs) between breast cancer patients (BCP) and healthy controls, we applied a Wilcoxon rank sum test, determining 77 CpGDMs positions after correction for multiple testing (Table 1). This panel of identified CpGDMs was able to cluster BCP and healthy controls separately using a hierarchical cluster approach (Fig. 1A). These results indicate the existence of CpG methylation differences at specific sequences between cancer patients and controls at the leukocyte level, which can be visualized by unsupervised classification techniques and could function as a breast cancer signature in blood
Summary
Breast cancer is a complex and heterogeneous disease caused by the interactions of both genetic and non-genetic factors. DNA methylation is potentially modifiable and is related to age, the strongest breast cancer risk predictor [2]. Alterations in DNA methylation patterns, both at the global genomic level and loci-specific, have been successfully explored as molecular biomarkers in cancer management [3]. We found a negative correlation between African ancestry and global DNA methylation in cancer patients, suggesting that the ancestral genome structure generated by the admixture process in the Uruguayan population influences DNA methylation patterns [4]. This underscores the importance of searching for population-specific DNA methylation markers for sporadic breast cancer
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