Abstract RF1-05: DNA methylation patterns are similar in benign tissue from ipsilateral and contralateral breast while different from matched breast cancer, and healthy controls

Résumé fourni par la source

Abstract Introduction: Epigenetic changes play a crucial role in cancer development. Among these, DNA methylation is one of the most significant due to its impact on gene expression and genome stability. Hyper-methylation generally suppresses transcription and hypo-methylation promotes it. In breast cancer research, tumor-adjacent tissue is often used as a reference for characterizing epigenetic alterations, but numerous studies suggest that the tissue adjacent to a tumor shares genomic characteristics with the tumor itself. The extent to which epigenetic profiles overlap between tumor, histologically normal tissues from the involved and uninvolved breast, and benign tissues from cancer-free individuals is unknown. Our study aims to address this gap by systematically comparing the DNA methylation profiles across these different tissue types. Methods: A total of 72 cancer patients were selected from Northwestern University, while data from 182 cancer-free women was obtained from tissue donated to the Komen Tissue Bank. From each individual cancer patient, four regional samples were collected: tumor tissue (TU), tumor-adjacent normal tissue (AN), benign tissue from the opposite quadrant of the involved breast (OQ), and benign tissue from the contralateral uninvolved breast (CUB). From cancer-free patients, normal breast tissue was collected (CFN). From these, we created a “tumor proximity axis”: CFN→CUB →OQ→AN→TU. Methylation profiles were assayed using Illumina’s Infinium Methylation EPIC v1.0 BeadChip. Differential methylation analysis was conducted in two sets of four pairwise comparisons: (1) comparing tumor samples to the four benign tissue categories, and (2) comparing tissue categories that are adjacent along the tumor proximity axis. The differentially methylated CpGs were analyzed for enrichment of transcription factor binding sites (TFBS) and genes. Results: Following data processing and quality control, there were 72 TU, 63 AN, 70 OQ, 72 CUB, and 182 CFN samples for analysis. Differential methylation analysis showed that TU samples had distinct methylation profiles, with more hypomethylation events compared to hypermethylation events relative to benign tissues. Case-benign tissues (AN, OQ, CUB) exhibited similar methylation profiles, distinct from CFN. Transcription factor binding site (TFBS) enrichment analysis revealed that case-benign samples, even those distant from tumor, i.e. CUB, showed breast cancer-related methylation changes. Hypomethylated sites in CUB compared to CFN were enriched for TF binding sites TP63, GATA3, ESR1, PR, AR, NR3C1, and GREB1. TU hypermethylation events were enriched for Polycomb-repressive complex 2 (PRC2) binding, including EZH2, SUZ12, and JARID2. ER+ and ER- tumors had distinct methylation profiles. Both ER+ and ER- tumors showed hypermethylation enrichment for PRC2-related binding motifs. However, hypomethylation events differed, with ER+ tumors enriched for hormone receptor-related pathways and ER- tumors enriched for hematopoiesis/immune-related pathways. We did not find any differential methylation between benign tissues from patients with ER+ vs. ER- tumors. Conclusions: DNA methylation changes profoundly at two points on the tumor proximity axis: CFN to CUB and AN to TU. Specifically, all case-benign tissues, including CUB, exhibited changes associated with breast cancer when compared to CFN. Although the methylation profiles of ER+ and ER- tumors differed, benign tissues showed no differences as a function of ER status of the tumor. These findings demonstrate that benign case tissue is not epigenetically “normal” and provide insights for further investigation into the process of tumorigenesis. Citation Format: Saya Dennis, Takahiro Tsukioki, Gannon Cottone, Wanding Zhou, Yuan Luo, Patricia A. Ganz, Mary E. Sehl, Seema Khan, Susan Clare. DNA methylation patterns are similar in benign tissue from ipsilateral and contralateral breast while different from matched breast cancer, and healthy controls [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF1-05.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.