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Epigenome analysis of normal ductal breast samples and infiltrating ductal breast cancer (BC) classified by tumour subtype

ABSTRACT: Genome wide DNA methylation profiling of non-tumoral and infiltrating ductal breast cancer (tumoral) samples. The HumanMethylation450 BeadChip was used to obtain DNA methylation profiles across approximately 450,000 CpG in non-tumoral and tumoral samples. Non-tumoral samples included six frozen non-neoplastic breast tissues from reduction mammoplasties and tumoral samples included eight frozen tumors from each BC subtype, i.e. luminal A (LA), luminal B (LB), luminal-HER2 (LH), HER2 (H) and triple-negative (TN) (Total: 40 tumors).

ORGANISM(S): Homo sapiens

PROVIDER: GSE141338 | GEO | 2020/02/17

REPOSITORIES: GEO

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Project description:Breast cancers display a high degree of diversity between and within tumors due to variations in both tumor cells and non-malignant cells of the tumor microenvironment (TME). While most studies on the TME have focused on stroma located within the tumor mass, few studies have examined the peri-tumoral microenvironment, which extends beyond the tumor margins and includes the surrounding, benign-appearing tissues. Here, we examined the heterogeneity in tumors and peri-tumoral stroma from 10 ER+PR+HER2- invasive breast carcinomas, through multi-region transcriptomic profiling. Tumor samples were obtained from the center, superior, inferior, medial, and lateral (C, S, Inf, M, L) regions of each tumor. Peritumoral samples were obtained from four radial directions corresponding to the regions the tumor samples were collected from (S, Inf, M, L) and from three zones of increasing distances from the tumor margins (Zone 1: 1-3 cm, Zone 2: 3-5 cm, Zone 3: 5-7 cm). To represent the normal breast transcriptomic state, 5 non-directional samples were each obtained from 3 non-tumor bearing breasts (NTB) - 1 patient had undergone cosmetic reduction mammoplasty and 2 patients were germline BRCA2-mutation carriers who had undergone risk-reducing mammoplasties. Total RNA was isolated and microarray was performed using the human Clariom™ S Assay (ThermoFisher Scientific). In total, 144 transcriptomic profiles (47 Tumor, 82 peri-tumoral stroma, 15 NTB) were analyzed. Heterogeneity was observed both within and between the tumor samples, highlighting that unlike the histological classification, an individual tumor is often comprised of several molecular sub-types. Similarly, the peri-tumoral stroma was also heterogeneous, albeit independent of the tumor heterogeneity. Four distinct stromal clusters were noted, which differed in their molecular pathways and cell type composition. Among these, the adipose-enriched stroma that had inflammatory cancer-associated fibroblasts and innate immune cells was significantly associated with poorer overall survival, in contrast to the myofibroblast-enriched stroma. These data together suggest that the peri-tumoral heterogeneity may be an important determinant of the evolution and treatment of breast cancers.

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Epigenome analysis of normal ductal breast samples and infiltrating ductal breast cancer (BC) classified by tumour subtype

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