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Genomic, transcriptomic and epigenomic characterization of multifocal breast cancer

ABSTRACT: A significant proportion of breast cancer patients develop multiple synchronous unilateral breast tumors, also referred to as multifocal tumors, which represent a diagnostic and therapeutic challenge. Multifocality has been associated with a possible adverse patient outcome, propensity for axillary nodal involvement, and increased risk of local recurrence following breast conserving surgery when compared to unifocal tumors. Previous studies indicate that most lesions from multifocal tumors are concordant with regard to the currently used pathological parameters (histological subtype and grade, hormonal receptors and HER2 status). However, to our knowledge, no study has yet provided a detailed molecular analysis of multifocal breast cancer. Here, we aimed to better define the incidence of multifocal breast cancer using a systematic analysis of pathology reports of primary breast cancers and to compare different foci from 5 multifocal breast cancers in a global analysis using genomic, transcriptomic and epigenomic data. We demonstrate that multifocality is a frequent finding since it concerns 22% (945/4340) of breast cancer patients with primary ductal breast cancer. We find that different lesions from multifocal breast cancer can differ at the (epi)genomic and transcriptomic level even when the foci present similar histology, grading, hormonal and HER2 status despite having a common genetic background. Since the number of (epi)genetic alterations with potential clinical utility is rapidly growing due to increasing numbers of targeted therapies, these findings suggest that it might be necessary to interrogate the different lesions of multifocal breast cancers for adequate treatment management of these tumors. The biological characterization of multifocal breast cancer here is focused on 5 cancers for which the foci did not differ in terms of histological grade, hormonal receptors and HER2 status. The characterization of multifocal tumors involved the identification of somatic rearrangements in 2 foci from each patient via low-coverage whole genome sequencing. Putative rearrangements were amplified by polymerase chain reaction (PCR) and capillary sequenced in tumor and matching blood-derived germline DNA to validate the somatic rearrangements. For all patients, the presence of a number of validated rearrangements was assessed in different paraffin blocks of tumor-adjacent histologically normal tissue by nested PCR. We also performed transcriptomic and epigenomic profiling in 4 and 5 patients respectively using the HG-U133 Plus 2.0 Chips and Infinium Methylation 450K arrays (RNA was not available for patient E).

ORGANISM(S): Homo sapiens

PROVIDER: GSE39451 | GEO | 2018/12/21

REPOSITORIES: GEO

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Project description:Hormones and growth factors accelerate cell proliferation of breast cancer cells, and these molecules are well investigated targets for drug development and application. The mechanisms of cell proliferation of breast cancers lacking estrogen receptor (ER) and HER2 have not been fully understood. The purpose of the present study is to find genes that are differentially expressed in breast cancers and that might significantly contribute to cell proliferation in these cancers. Forty tumor samples, consisting of ten each of immunohistochemically ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) cancer were analyzed using oligonucleotide microarrays. Both genes and tumor samples were subjected to hierarchical clustering. ER(+)/HER2(-) breast cancers and ER(-)/HER2(-) cancers tended to form a tumor cluster, but HER2 positive breast cancers were split into different tumor clusters. Significant differential expression between IHC-ER(-)/HER2(-) and other tumors was defined as having an expression level at least 2-fold higher or 2-fold lower, and analyzed by multi-step two-way ANOVA. Genes overexpressed differently in IHC-ER(-)/HER2(-) breast cancers compared to other all three types were 8 genes (FABP7, GABRP, GAL, CXCL13, CDC42EP4, C2F, FOXM1, CSDA), and underexpressed genes were nine including ITGB5, KIAA0310, MAGED2, PRSS11, SORL1, TGFB3, KRT18, CPE, BCAS1. No gene was directly related to cell proliferation such as cyclins, cyclin-dependent kinase, p53, p16, and the pRb and p21 families. We had a particular focus on a transcriptional factor E2F-5 from a list of genes overexpressed in ER negative breast cancers compared to ER positive breast cancers, and further examined. Gene amplification of E2F-5 was detected in 5/57 (8.8%) in breast cancers by FISH. No point mutation was found at the binding domain with DNA or dimerization partner of E2F-5. Immunohistochemically E2F-5 positive cancers were more frequent in ER(-)/HER2(-) cancer (14/27, 51.9%) than in other types of cancer (5/30, 16.7%) (p=0.05). E2F-5 positive cancers had higher Ki-67 labeling index (59.5%) than E2F-5 negative cancers (36.3%). E2F-5 positive cancers showed higher histological grade including metaplastic carcinoma, and worse clinical outcome with shorter disease free survival in node negative patients. In conclusion, we demonstrated that there is a population of breast cancer with overexpression of a cell cycle related transcriptional factor E2F-5. E2F-5 positive breast cancers were frequent in ER(-)/HER2(-) group with high Ki-67 labeling index, high histological grade and worse clinical outcome. Keywords: immunohistochemical phenotype

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Genomic, transcriptomic and epigenomic characterization of multifocal breast cancer

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