Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF et al.. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7: 96

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
BMC Genomics (Impact Factor: 3.99). 02/2006; 7(1):96. DOI: 10.1186/1471-2164-7-96
Source: PubMed


Validation of a novel gene expression signature in independent data sets is a critical step in the development of a clinically useful test for cancer patient risk-stratification. However, validation is often unconvincing because the size of the test set is typically small. To overcome this problem we used publicly available breast cancer gene expression data sets and a novel approach to data fusion, in order to validate a new breast tumor intrinsic list.
A 105-tumor training set containing 26 sample pairs was used to derive a new breast tumor intrinsic gene list. This intrinsic list contained 1300 genes and a proliferation signature that was not present in previous breast intrinsic gene sets. We tested this list as a survival predictor on a data set of 311 tumors compiled from three independent microarray studies that were fused into a single data set using Distance Weighted Discrimination. When the new intrinsic gene set was used to hierarchically cluster this combined test set, tumors were grouped into LumA, LumB, Basal-like, HER2+/ER-, and Normal Breast-like tumor subtypes that we demonstrated in previous datasets. These subtypes were associated with significant differences in Relapse-Free and Overall Survival. Multivariate Cox analysis of the combined test set showed that the intrinsic subtype classifications added significant prognostic information that was independent of standard clinical predictors. From the combined test set, we developed an objective and unchanging classifier based upon five intrinsic subtype mean expression profiles (i.e. centroids), which is designed for single sample predictions (SSP). The SSP approach was applied to two additional independent data sets and consistently predicted survival in both systemically treated and untreated patient groups.
This study validates the "breast tumor intrinsic" subtype classification as an objective means of tumor classification that should be translated into a clinical assay for further retrospective and prospective validation. In addition, our method of combining existing data sets can be used to robustly validate the potential clinical value of any new gene expression profile.

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    • " this previous study , both support the hypothesis that tobacco smoking impacts the germ cell apoptotic process . Indeed , it has been shown that although discordances may be found between data sets for the same biological process , common patterns of expression and outcome predictions can be identified in data sets generated by independent labs [ Hu et al . 2006 ] . However , it should be stressed that further studies with independent samples are required to clarify how smoking affects spermatozoa mRNA profiles ."
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    ABSTRACT: Spermatozoa contain a complex population of RNAs including messenger RNAs (mRNAs) and small RNAs such as microRNAs (miRNA). It has been reported that these RNAs can be used to understand the mechanisms by which toxicological exposure affects spermatogenesis. The aim of our study was to compare mRNA and miRNA profiles in spermatozoa from eight smokers and eight non-smokers, and search for potential relationships between mRNA and miRNA variation. All men were selected based on their answers to a standard toxic exposure questionnaire, and sperm parameters. Using mRNA and miRNA microarrays, we showed that mRNAs from 15 genes were differentially represented between smokers and non-smokers (p < 0.01): five had higher levels and 10 lower levels in the smokers. For the microRNAs, 23 were differentially represented: 16 were higher and seven lower in the smokers (0.004 ≤ p < 0.01). Quantitative RT-PCR confirmed the lower levels in smokers compared to non-smokers for hsa-miR-296-5p, hsa-miR-3940, and hsa-miR-520d-3p. Moreover, we observed an inverse relationship between the levels of microRNAs and six potential target mRNAs (B3GAT3, HNRNPL, OASL, ODZ3, CNGB1, and PKD2). Our results indicate that alterations in the level of a small number of microRNAs in response to smoking may contribute to changes in mRNA expression in smokers. We conclude that large-scale analysis of spermatozoa RNAs can be used to help understand the mechanisms by which human spermatogenesis responds to toxic substances including those in tobacco smoke.
    Systems biology in reproductive medicine 03/2015; 61(3):1-11. DOI:10.3109/19396368.2015.1022835 · 1.60 Impact Factor
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    • "Basal cells exhibit mesenchymal features and are more contractile and motile than luminal epithelial cells. A number of gene expression profiling studies of various breast cancer samples has identified gene signatures characteristic of basal-like breast cancers (aggressive, highly metastatic, often triple-negative) and luminal-like breast cancers, which have a better prognosis [Hu et al., 2006; Rakha et al., 2008]. Investigation of gene expression signatures in a sample set of basal-like breast tumors showed a correlation between Myo1e expression level and poor prognosis in patients with basal-like breast cancer [Hallett et al., 2012]. "
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    Cytoskeleton 08/2014; 71(8). DOI:10.1002/cm.21187 · 3.12 Impact Factor
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    • "In (A) subtypes classification was either performed using a single marker method according to Hugh et al. (Hugh et al., 2009) among 4467 pre-therapeutic invasive breast cancer samples from 40 datasets. In (B) the centroid method using the intrinsic gene set (Weigelt et al., 2010; Hu et al., 2006) was applied to 1142 samples from six large datasets. Highest expression of ASAH1 was detected in the Luminal A subtype of breast cancer by both methods. "
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    ABSTRACT: Acid ceramidase (ASAH1) a key enzyme of sphingolipid metabolism converting pro-apoptotic ceramide to sphingosine has been shown to be overexpressed in various cancers. We previously demonstrated higher expression of ASAH1 in ER positive compared to ER negative breast cancer. In the current study we performed subtype specific analyses of ASAH1 gene expression in invasive and non invasive breast cancer. We show that expression of ASAH1 is mainly associated with luminal A - like cancers which are known to have the best prognosis of all breast cancer subtypes. Moreover tumors with high ASAH1 expression among the other subtypes are also characterized by an improved prognosis. The good prognosis of tumors with high ASAH1 is independent of the type of adjuvant treatment in breast cancer and is also detected in non small cell lung cancer patients. Moreover, even in pre-invasive DCIS of the breast ASAH1 is associated with a luminal phenotype and a reduced frequency of recurrences. Thus, high ASAH1 expression is generally associated with an improved prognosis in invasive breast cancer independent of adjuvant treatment and could also be valuable as prognostic factor for pre-invasive DCIS.
    Molecular Oncology 07/2014; 9(1). DOI:10.1016/j.molonc.2014.07.016 · 5.33 Impact Factor
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