Association between genome‐wide DNA methylation pattern and response to trastuzumab in HER2‐positive breast cancer patients

Abstract

IntroductionThe administration of trastuzumab has led to significant improvement in survival of HER2‐positive breast cancer patients in the adjuvant and metastatic settings. Trastuzumab resistance, however, has been increasingly recognized as a major obstacle. Recent evidence suggests that epigenetic mechanisms might be associated with acquired resistance to cancer therapies. Aim of this study was to explore the association between genome‐wide DNA methylation pattern in breast cancer tissue and the response to trastuzumab.Patients and methodsDNA methylation pattern was assessed in breast cancer tissues of trastuzumab‐treated HER2‐positive breast cancer patients who acquired resistance to treatment (case group, n=6) and compared to that of trastuzumab‐treated HER2‐positive breast cancer patients who did not develop resistance (control group, n=6) using the Illumina Infinium HumanMethylation450 BeadChip. Cases were matched to controls for several factors. Bioinformatics analyses were performed using the R statistical environment (robust linear regression method) to identify differentially methylated genes (DMGs) (FDR < 0.05) between case and control groups.ResultsCompared to the control group, in the matched case group we identified 879 hypermethylated and 293 hypomethylated genes. The differentially methylated set of genes was enriched in molecular and cellular functions associated with cellular movement (P=8.02E‐07) as well as cell death and survival (P=4.24E‐09). Pathways associated with ERK/MAPK signaling and regulation of the epithelial‐mesenchymal transition were overrepresented (P=2.13E‐05, and P=2.43E‐03, respectively). Among the DMGs we observed AGPAT1, a gene related to the PI3K‐mTOR pathway which has been reported to be implicated with trastuzumab resistance in addition to be differentially expressed between HER2‐positive breast cancer patients who responded to trastuzumab and those who acquired resistance.ConclusionsAlthough our sample size was small, we observed DMGs associated with the response to trastuzumab. These data need to be confirmed in a larger prospective cohort of trastuzumab‐treated HER2‐positive breast cancer patients.Support or Funding InformationDF received doctoral fellowships from the Fonds de recherché du Québec – Santé (FRQS) and the Laval University Cancer Research Center. CD is a recipient of the Canadian Breast Cancer Foundation‐Canadian Cancer Society Development award (award #703003) and the FRQS Research Scholar.This study was supported by the Fondation des Hôpitaux Enfant Jésus – St‐Sacrement. Clinical specimens were provided by the Fondation du cancer du sein du Québec and the Banque de tissus et de données of the Réseau de recherche sur le cancer of the FRQS, which is affiliated with the Canadian Tumour Repository Network.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.