Study finds DNA methylation profile for early breast cancer detection

Researchers from Singapore have found a whole blood-based DNA methylation biomarker profile that effectively distinguishes breast cancer patients from healthy controls.

“[W]e have identified a breast cancer-associated methylation profile comprising 51 CpGs from Asian patients,” said the researchers. “In a machine learning algorithm, this methylation profile can distinguish Asian breast cancer cases from healthy controls better than previously reported breast cancer-associated methylation profiles.”

DNA methylation profiling was conducted in 524 Chinese women (median age 40 years). Of these, 256 had breast cancer, while 268 were age- and ethnicity-matched healthy controls. Peripheral blood samples were collected from the National Cancer Centre Singapore, National University Hospital, Tan Tock Seng Hospital, and Lucence Diagnostics (cancer cohort) and KK Women’s and Children’s Hospital and SingHealth Outram and Bukit Merah Polyclinics (unaffected controls).

The independent test set comprising 75 cancer patients and 81 noncancer controls showed that the selected methylation profile with xgbTree could distinguish cancer patients from healthy controls with 75 percent sensitivity, 78 percent specificity, and an area under the curve of 0.827. [Clin Epigenetics 2024;16:66]

In the transcription factor enrichment analysis (aggregated q value<0.05), there was an enrichment of transcription factors from the multifunctional AP-1 transcription factor family, which has roles in the immune system’s different properties, including immune response against cancer. [Cancers (Basel) 2019;11:1037]

In the pathway enrichment analysis of the top 10 enriched pathways, there was an enrichment of immune-related pathways associated with interleukin(IL)-12, IL-21, T helper (T_h) 17 cell lineage commitment, and natural killer (NK) cell activation.

The top 10 enriched pathways are positive regulation of IL-12 production, IL-21-mediated signalling pathway, response to IL-21, cellular response to IL-21, IL-12 production, regulation of IL-12 production, positive regulation of T_h17 cell lineage commitment, regulation of defence response to virus, NK cell activation, and protein initiator methionine removal involved in protein maturation.

The researchers said that the findings from the two enrichment analyses suggest that the host immune response against cancer may have contributed to the difference between the methylation profiles of breast cancer cases and healthy controls.

May augment or supplant existing technologies

While effective for early cancer detection, screening mammograms and clinical breast examinations may deliver false positives and overdiagnoses. [N Engl J Med 1998;338:1089–1096; Eur J Cancer 2000;36:1089–1097; Health Aff 2015;34:576–583] “Blood-based cancer biomarkers show great promise in supplementing or replacing these technologies,” the researchers pointed out.

“The development of an accurate blood-based biomarker assay for early detection of breast cancer has the potential to drastically reduce the costs associated with false positives and overdiagnosis in current screening programmes and, more importantly, overall breast cancer mortality,” they said.

They noted that they chose peripheral blood DNA methylation as it is easy to collect and process, especially relative to cell-free DNA.

“Furthermore, we provide evidence for a plausible mechanism in the immune response against cancer as the driver behind the association of whole blood-methylation profiles and breast cancer,” they added.

Of note, the methylation profile identified in the study trumped four others that have been identified previously in predominantly European cohorts. [Nat Commun 2018;9:867; JNCI J Nat Cancer Inst 2020;112:87–94; JNCI J Nat Cancer Inst 2020;112:295–304; Mol Oncol 2022;16:42–53]

However, the investigators underlined some limitations that should be taken into context, such as the potential confounding from storage duration or treatment effects. They added that the applicability of the findings to early detection of sporadic breast cancer should be taken with caution, as participants had either early-onset and/or a family history of breast cancer.