DNA methylation markers panel can improve prediction of response to neoadjuvant chemotherapy in luminal B breast cancer

Abstract

Despite the advantages of neoadjuvant chemotherapy (nAct), associated toxicity is a serious complication that renders monitoring of the patients' response to nAct highly important. thus, prediction of tumor response to treatment is imperative to avoid exposure of potential non-responders to deleterious complications. We have performed genome-wide analysis of DnA methylation by XmaI-RRBS and selected CpG dinucleotides differential methylation of which discriminates luminal B breast cancer samples with different sensitivity to NACT. With this data, we have developed multiplex methylation sensitive restriction enzyme pcR (MSRe-pcR) protocol for determining the methylation status of 10 genes (SLC9A3, C1QL2, DPYS, IRF4, ADCY8, KCNQ2, TERT, SYNDIG1, SKOR2 and GRIK1) that distinguish BC samples with different NACT response. Analysis of these 10 markers by MSRE-PCR in biopsy samples allowed us to reveal three top informative combinations of markers, (1) IRF4 and C1QL2; (2) IRF4, C1QL2, and ADCY8; (3) IRF4, C1QL2, and DPYS, with the areas under Roc curves (AUCs) of 0.75, 0.78 and 0.74, respectively. A classifier based on IRF4 and C1QL2 better meets the diagnostic panel simplicity requirements, as it consists of only two markers. Diagnostic accuracy of the panel of these two markers is 0.75, with the sensitivity of 75% and specificity of 75%.

Deciphering the Methylation Landscape in Breast Cancer: Diagnostic and Prognostic Biosignatures through Automated Machine Learning

“…DNA methylation is the most studied epigenetic mechanism that is highly involved in the regulation of gene expression in BrCa cells [3]. Aberrant methylation in BrCa tissues or in liquid biopsies has been characterized and correlated to diagnosis [4][5][6], prognosis [7][8][9] and the prediction of treatment response [10,11], leading to emerging biomarkers in the BrCa management cascade. Recently, the introduction of genome-wide methylation analyses enables the simultaneous study of up to hundreds of thousands of CpG sites, and produces highdimensional datasets which can allow in-depth understanding of the events of methylation in BrCa pathogenesis, as well as its translation to clinical solutions.…”

Molecular Pap Smear: Validation of HPV Genotype and Host Methylation Profiles of ADCY8, CDH8, and ZNF582 as a Predictor of Cervical Cytopathology

“…Published literature on promoter methylation of ADCY8, CDH8 , and ZNF582 has expanded recently and hypermethylation of one or more of these loci have been found in cancers of the breast, oropharynx, esophagus, and anus ( Tang et al, 2019 ; Ekanayake Weeramange et al, 2020 ; Sigin et al, 2020 ; van der Zee et al, 2020 ). These reports not only support the validity of these epigenetic modifications as cancer biomarkers but inform a broader application beyond cervical cancer.…”

“…First, differential methylation of ADCY8 was identified as one of three most informative biomarkers in luminal B breast cancer from a cohort of Russian women. Methylation status of these markers were predictive of response to neoadjuvant chemotherapy before surgery which may be applicable as a clinical test to guide therapy ( Sigin et al, 2020 ). Second, CDH8 promoter hypermethylation has been documented in four head and neck cancer studies ( Ekanayake Weeramange et al, 2020 ).…”

DNA methylation as predictive marker of response to immunotherapy?

“…Several studies revealed that DNA methylation profiling may serve as novel tool in oncology for improved classification and differential diagnosis of carcinomas, especially brain tumors and sarcomas [26,27]. Moreover, the potential of DNA methylation pattern as prognostic or predictive marker of response to specific therapies including chemotherapy, targeted therapy and immunotherapy in several tumor types was reported previously [28][29][30].…”