Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Oligonucleotide Array CGH Profiles of Breast Cancer Patients Treated with High Dose or Conventional Chemotherapy

ABSTRACT: DNA copy number profiles can identify patients with a defect in BRCA1 or BRCA2. We previously showed that patients with a BRCA1 like profile benefit from intensified alkylating chemotherapy (IA, 4 cycles 5-fluorouracyl (5FU), epirubicin, cyclophosphamide (C) + 1 cycle carboplatin, thiotepa and cyclophosphamide with autologous stem cell transplantation (ASCT)). Presumably, this is because of the defect in error free homologous recombination DNA repair. Here we present an independent study IA chemotherapy (2 cycles induction, followed by ifosfamide, 12 g/m2; carboplatin, 900 mg/m2; and epirubicin, 180 mg/m2 with ASCT) versus anthracyclin-C (AC) or C-methothrexate-5FU (CMF) regimens in high risk breast cancer. DNA isolated from untreated resection specimens of 117 patients was labeled using Enzo labeling kit for array CGH and hybridized to a custom 135k Nimblegen platform.

ORGANISM(S): Homo sapiens

SUBMITTER: Philip Schouten

PROVIDER: E-GEOD-50407 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Breast cancers with a BRCA1-like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy.

Schouten Philip C PC Marmé Frederik F Aulmann Sebastian S Sinn Hans-Peter HP van Essen Hendrik F HF Ylstra Bauke B Hauptmann Michael M Schneeweiss Andreas A Linn Sabine C SC

Clinical cancer research : an official journal of the American Association for Cancer Research 20141205 4

<h4>Purpose</h4>Breast cancers in carriers of inactivating mutations of the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This signature is shared with cancers that inactivate BRCA1 through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.<h4>Experimental design</h4>W ...[more]

PMID: 25480832

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Project description:This phase I/II neoadjuvant trial determined maximally-tolerated doses (MTD), dose-limiting toxicities (DLT), response-to-therapy, and explored the role of new response biomarkers. The combination regimens were delivered with acceptable toxicity, good clinical response, inducing changes in tumor RNA content and integrity. Pre-treatment gene expressions impacted clinical response, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness. The NCIC Clinical Trials Group MA.22 phase I/II clinical trial (ClinicalTrials.gov identifier NCT00066443) sought to determine the optimal dosing regimens for docetaxel/epirubicin combination chemotherapy in women with locally advanced (over 95% of patients) or inflammatory breast cancer. The protocol was approved by Health Canada and local Ethics Review Boards, and patients provided written, informed consent. Various doses of epirubicin and docetaxel were administered to patients in either a standard q3 weekly (Schedule A) or dose dense q2 weekly (Schedule B) regimen. Doses for Schedule A were 75 mg/m2 IV of docetaxel and 75, 90, 105, or 120 mg/m2 IV of epirubicin (with 6 mg of pegfilgrastim per cycle on day 2 to prevent neutropenia). Doses for both docetaxel and epirubicin in Schedule B were 50, 60, and 70 mg/m2 IV (with identical pegfilgrastim support). For each schedule, phase I was dose finding for phase II. Patients were allocated to the various phases and dosing regimens of the trial without randomization. None of the patients received trastuzumab in the initial years of the study and HER2+ patients were not enrolled on study, once trastuzumab funding became available. Six tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 cores for pathologic assessment; 3 cores for microarray studies. Total RNA was isolated from these cores and RNA integrity was assessed using Agilent Bioanalyzer. One of the RNA samples with the best quality was used for microarray study. One colour microarray of Agilent whole human genome nucleotide arrays was conducted with one array per patient. The current data set represents pre-treatment set. MA.22 clinical trial accrued T3N0, any N2 or N3, and T4 breast cancer patients (according to the classification described at; http://emedicine.medscape.com/article/2007112-overview). However, since the current study does not focus on the tumor grade/stage, the information was not provided in the current records.

Project description:Background/Objectives: Obese subjects have increased number of enlarged fat cells which are reduced in size but not number in post-obesity. We performed DNA methylation profiling in fat cells with the aim of identifying differentially methylated DNA sites (DMS) linked to adipose hyperplasia (many small fat cells) in post-obesity. Subjects/Methods: Genome-wide DNA methylation was analyzed in abdominal subcutaneous fat cells from 16 women examined two years after gastric bypass surgery at a post-obese state (BMI 26±2 kg/m2, mean±s.d.) and 14 never-obese women (BMI 25±2 kg/m2). Gene expression was analyzed in subcutaneous adipose tissue from 9 women in each group. In a secondary analysis, we examined DNA methylation and expression of adipogenesis genes in 15 and 11 obese women, respectively. Results: The average degree of DNA methylation of all analyzed CpG-sites was lower in fat cells from post-obese as compared to never-obese women (P=0.014). 8,504 CpG sites were differentially methylated in fat cells from post-obese versus never-obese women (false discovery rate 1%). DMS were under-represented in CpG-islands and surrounding shores. The 8,504 DMS mapped to 3,717 unique genes; these genes were over-represented in cell differentiation pathways. Notably, 27% of genes linked to adipogenesis (i.e. 35 of 130) displayed DMS (adjusted P=10−8) in post-obese versus never-obese women. Next, we explored DNA methylation and expression of genes linked to adipogenesis in more detail in adipose tissue samples. DMS annotated to adipogenesis genes were not accompanied by differential gene expression in post-obese compared to never-obese women. In contrast, adipogenesis genes displayed differential DNA methylation accompanied by altered expression in obese women, Conclusions: Global CpG hypomethylation and overrepresentation of DMS in adipogenesis genes in fat cells may contribute to adipose hyperplasia in post-obese women. Post obese=16, Control group=14.

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Project description:Recent studies have suggested that elevated expression of aldoketoreductase (AKR) 1C1 or 1C2 in tumour cells is associated with increased resistance to DNA damaging agents such as cisplatin and doxorubicin. However, it has not been shown whether selection of tumour cells for resistance to DNA-damaging anthracyclines actually results in increased expression of AKRs and increased conversion of anthracyclines to 10-fold less toxic 13-hydroxy metabolites. It is also unclear whether the induction of aldokeoreductases is temporally correlated with the onset of anthracycline resistance and whether there is a direct relationship between the level of AKR expression or activity and the magnitude of drug resistance. Through microarray profiling of MCF-7 breast cancer cells selected for progressive resistance to doxorubicin or epirubicin, we have identified several genes whose expression has been correlated with both the onset and magnitude of drug resistance, including a “1C” AKR. AKR 1C overexpression was verified by quantitative PCR. Also associated with the onset of anthracycline resistance were genes involved in drug transport (ABCB1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), ROS protection (TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). Consistent with the role of AKRs in anthracycline resistance, doxorubicin- and epirubicin-resistant breast tumour cells exhibited 2.2-fold and 6.1-fold higher levels of the 13-hydroxy metabolite of doxorubicin (doxorubicinol) than wildtype MCF-7 cells. In addition, an inhibitor of AKR 1C2 (5- cholanic acid) almost completely restored sensitivity to doxorubicin in Abcb1-deficient doxorubicin-resistant cells, while having no effect on Abcb1-expressing epirubicin-resistant cells. Taken together, our findings strongly suggest the involvement of multiple genes in the acquisition of anthracycline resistance in breast tumor cells---in particular redox genes such as the 1C AKRs. Keywords: Drug resistance of breast cancer cells In order to identify genes whose expression strongly correlates with the acquisition or magnitude of drug resistance or are temporally related with the acquisition of resistance, we selected MCF-7 breast tumor cells for survival in increasing concentrations (doses) of doxorubicin or epirubicin. Panels of cells exhibiting progressive resistance to either doxorubicin (MCF-7DOX-2) or epirubicin (MCF-7EPI) were obtained. Cells were also “selected” in the absence of drug at each step during selection to serve as co-cultured control (MCF-7CC) cells. In this study, we have used cDNA microarray analysis of these cell lines to identify a variety of “redox” genes whose expression can be correlated with the acquisition or magnitude of drug resistance in MCF-7DOX-2 and MCF-7EPI cells, including a “1C” aldoketoreductase (AKR).

Dataset Information

Oligonucleotide Array CGH Profiles of Breast Cancer Patients Treated with High Dose or Conventional Chemotherapy

Publications

Breast cancers with a BRCA1-like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy.

Similar Datasets

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