Abstract 93P
Background
Studying cancer-specific abnormal DNA methylation promises the development of novel laboratory diagnostic tests, including those to predict efficacy of neoadjuvant chemotherapy (NACT). Recent progress in genome-wide DNA methylation profiling by bisulfite sequencing facilitates identification of clinically relevant diagnostic markers.
Methods
Genome-wide methylation analysis of 37 breast cancer biopsy specimens of the luminal B subtype taken before the treatment was performed using the XmaI-RRBS method. Informative DNA methylation markers were selected from XmaI-RRBS data using the Wilcoxon–Mann–Whitney test. To evaluate the discriminative potential of markers, we have calculated the difference in methylation frequencies, sensitivity, specificity and area under ROC curve for each marker. Cross-validation was used to characterize individual markers.
Results
Among the markers tested by XmaI-RRBS, methylation of a CpG island at the IRF4 (interferon regulatory factor 4) gene promoter has the highest discriminative potential with the methylation frequency of 20% in a group of breast carcinomas that demonstrated stable disease after NACT versus 70% in a group of tumors with partial response. Diagnostic accuracy of IRF4 promoter DNA methylation marker in relation to NACT effect is 0.75, with the sensitivity of 80% and specificity of 70%.
Conclusions
Differential methylation of IRF4 gene promoter identified in this study predicts response of luminal B breast tumors to neoadjuvant anthracyclines and taxanes-based schemes, providing valuable predictive information even in a single-gene setting. Our results are biologically in line with previous reports of interferon regulatory factor 4 implication in cancer. It has also been previously demonstrated that IRF4 expression is downregulated by DNA methylation at its 5’ CpG island. Here we have presented the first evidence of possible application of its methylation as a predictive NACT efficacy marker for breast cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Federal State Budgetary Scientific Institution Research Centre of Medical Genetics.
Funding
Russian Science Foundation (project No.18-15-00430).
Disclosure
All authors have declared no conflicts of interest.