Project description:The diverse clinical outcomes of prostate cancer have led to the development of gene signature assays predicting disease progression. Improved prostate cancer progression biomarkers are needed as current RNA biomarker tests have varying success for high-risk prostate cancer. Interest grows in universal gene signatures for invasive carcinoma progression. Early breast and prostate cancers share characteristics, including hormone dependence and BRCA1/2 mutations. Given the similarities in the pathobiology of breast and prostate cancer, we utilized the NanoString BC360 panel, comprising the validated PAM50 classifier and pathway-specific signatures associated with general tumor progression as well as breast cancer-specific classifiers. This retrospective cohort of primary prostate cancers (n=53) was stratified according to biochemical recurrence status and the CAPRA-S to identify genes related to high-risk disease
Project description:Genome wide DNA methylation profiling of primary breast cancer tumors and their axillary metastasis and/or ipsilateral breast recurrence and/or contralateral breast recurrence. The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs. Samples included 20 primary breast tumors and their matched axillary metastasis, 17 primary breast tumors and their matched ipsilateral breast recurrence, and 11 primary breast tumors and their matched contralateral breast recurrence. Bisulphite converted DNA from the 96 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2 contributed by Institut Curie - Fabien Reyal
Project description:Genome wide DNA methylation profiling of primary breast cancer tumors and their axillary metastasis and/or ipsilateral breast recurrence and/or contralateral breast recurrence. The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs. Samples included 20 primary breast tumors and their matched axillary metastasis, 17 primary breast tumors and their matched ipsilateral breast recurrence, and 11 primary breast tumors and their matched contralateral breast recurrence.
Project description:Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1% to 10% of tumor cells should be regarded as hormone receptor positive tumors. However, clinical data shows that patients with such tumors have a worse outcome compared to patients with hormone receptor expression above 10 %. Further, gene expression studies suggest that these tumors have a TNBC-like signature similar to triple negative breast cancers (TNBC). The goal of this study was to use DNA methylation-based classification to clarify the status for this infrequent but important patient subgroup. We performed whole genome DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas. Unsupervised clustering and dimensionality reduction revealed that breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with TNBC reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs with almost no differential methylation. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples as well as clinical outcome parameters were more similar to TNBCs and differed from LowHR_HRpos-like cases. We here demonstrate that LowHR breast cancer comprises two molecularly distinct groups that can be separated by DNA methylation profiling. More clinical data is required for a definite classification of these tumors, but our data strongly suggests that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.
Project description:The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin–DNA–RNA–protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor–positive and –negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology.
PMID: 29921600 (Table S5 and Table S7)
Project description:Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations, which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we employed non-malignant random periareolar fine needle aspirates (RPFNA) in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of breast cancer patients included gene expression patterns, which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell number. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (p<0.001), and large tumor size (p=0.002), resulting in decreased recurrence-free patient survival (p<0.001). Our assays demonstrate a biological 'fingerprint' of probable prior exposure to endocrine disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome. Experiment Overall Design: The study included twelve patients undergoing breast biopsy or surgery for breast cancer. Random periareolar fine needle aspirates (RPFNA) were collected from the unaffected contralateral breast of these patients. Control and hormone treated RPFNA cell cultures were analyzed using Affymetrix GeneChip(TM) arrays
Project description:TP53 mutations are a poor prognostic factor in breast cancers. This study sets out to identify the gene set that determine expression signature of the TP53 status (TP53 signature) and to correlate it with clinical outcome. Using comprehensive expression analysis and DNA sequencing of the TP53 gene in 38 Japanese breast cancer patients, we have isolated a gene set of 33 genes from differentially expressed genes in the learning set (n=26), depending on the TP53 status. Predictive accuracy of TP53 status by gene expression profile was 83.3% in the test set (n=12). As independent external datasets, two published datasets were introduced for validation of TP53 status prediction (251 Swedish samples) and survival analysis (both the Swedish and 295 Dutch samples). TP53 signature has the ability to predict recurrence-free survival (RFS) of 29 stage I and II Japanese breast cancers (log rank, P = 0.032), and RFS, overall survival of two independently published datasets (log rank, both P < 0.0001). Multivariate analysis has shown an independent and significant prognostic factor with a hazard ratio (HR) for recurrence and survival in two external datasets (P < 0.0001). The TP53 signature is also a strong prognostic factor in the subgroups: estrogen-receptor positive, lymph node (LN) positive and negative, intermediate/high risk in St. Gallen criteria, and high risk in National Cancer Institute (NCI) criteria (log rank, P < 0.0001). TP53 signature is a reliable and independent predictor of the outcome of disease in operated breast cancer. Keywords: Tumor sample comparison
Project description:TP53 mutations are a poor prognostic factor in breast cancers. This study sets out to identify the gene set that determine expression signature of the TP53 status (TP53 signature) and to correlate it with clinical outcome. Using comprehensive expression analysis and DNA sequencing of the TP53 gene in 38 Japanese breast cancer patients, we have isolated a gene set of 33 genes from differentially expressed genes in the learning set (n=26), depending on the TP53 status. Predictive accuracy of TP53 status by gene expression profile was 83.3% in the test set (n=12). As independent external datasets, two published datasets were introduced for validation of TP53 status prediction (251 Swedish samples) and survival analysis (both the Swedish and 295 Dutch samples). TP53 signature has the ability to predict recurrence-free survival (RFS) of 29 stage I and II Japanese breast cancers (log rank, P = 0.032), and RFS, overall survival of two independently published datasets (log rank, both P < 0.0001). Multivariate analysis has shown an independent and significant prognostic factor with a hazard ratio (HR) for recurrence and survival in two external datasets (P < 0.0001). The TP53 signature is also a strong prognostic factor in the subgroups: estrogen-receptor positive, lymph node (LN) positive and negative, intermediate/high risk in St. Gallen criteria, and high risk in National Cancer Institute (NCI) criteria (log rank, P < 0.0001). TP53 signature is a reliable and independent predictor of the outcome of disease in operated breast cancer. Experiment Overall Design: Microarray hybridizations (Agilent: Whole Human Genome Oligo Microarray; 41k unique probe) were carried out with 1μg Cy3 labeled cRNA and 1 μg Cy5 labeled cRNA, both prepared from each sample and reference pool, respectively. Experiment Overall Design: Fluorescent intensities of scanned images were quantified by ArrayVision Ver.8 rev.4 (Imaging research). Experiment Overall Design: The gene expression data was quantified and analyzed by GeneSpring 6.2 (Silicon Genetics). To identify the TP53 status predictor gene set, a Wilcoxon rank sum test along with Benjamini and Hochberg false discovery rate (FDR) was used.