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Gene and microRNA expression profiling of breast tumors from Chinese and Italian women [gene]

ABSTRACT: Gene and miRNA profiles from a unique Chinese/Caucasian trans-ethnic collection of breast cancer from Shanghai (China) and Milan (Italy) were compared using an unsupervised approach that identified similar clusters of correlated features in Chinese and Caucasian datasets. Partition of gene expression data using previously published gene signatures, such as the PAM50 intrinsic gene list and the extracellular matrix (ECM) genes, revealed Chinese and Caucasian subgroups with equivalent gene and miRNA expression profiles. A significant reduction of Luminal-A tumors was observed in the Chinese series. Tissue samples from 78 Chinese (Han Chinese) and 97 Italian (South Europe Caucasian) consecutive primary breast tumors were subjected to gene and miRNA profiling. Tissue specimens, initially collected respectively in the Chinese and Italian hospitals, were all stored, randomly processed and analyzed in identical experimental conditions in the Italian center to minimize pre-analytical, instrumental and computational variability, enabling direct comparison of gene and miRNA profiles from the two groups.

ORGANISM(S): Homo sapiens

SUBMITTER: Dugo Matteo

PROVIDER: S-ECPF-GEOD-59590 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background: Breast cancer is a complex disease, encompassed by different clinically and molecularly stratified entities. In 2000, Perou and colleagues demonstrated that tumor phenotypic diversity correlates with differences in global gene expression patterns, which in turn reflect aspects of the biological behavior of the tumors. Gene expression profiling has distinguished sporadic breast tumor sub-classes with genetic, histopathological and clinical differences, however, little is known about the molecular classification of hereditary breast tumors. It has been recently suggested that most tumors arising in BRCA1 mutation carriers display a basal-like phenotype, with the percentages reported in different studies ranging from 44 to almost 100%. In the present study we used expression profiling to produce a molecular classification of BRCA1-associated breast tumors and applied an integrative approach to examine biological dependencies or differences. Methods and Findings: We used frozen tumor tissue from fourteen patients all of which harbored germline pathological mutations in BRCA1. Total RNA extraction, amplification and labeling with Cy5 were performed using standard protocols. Universal Human Reference RNA (Stratagene) was used as a reference and labeled with Cy3. Each pair of Cy3/Cy5 samples was hybridized onto the CNIO human OncoChip V2, which consists of a spotted microarray with 11,675 cDNA clones from the I.M.A.G.E. Consortium. Two channel ratios (Cy5/Cy3) for each spot were generated and quantified using GenePix Pro 5.1 (Axon Instruments, Inc., Union City, CA, USA). Data were normalized and filtered and multiple statistical analyses were performed. The data are deposited in the GEO database under the accession number GSE12350. A tissue microarray (TMA) containing an independent series of 15 BRCA1 tumors was used to validate some of the results obtained. We have described molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for Estrogen Receptor, ESR1. Signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumors was mainly linked to cell proliferation-related processes and, therefore, regulated by the estrogen receptor, while the signature of ESR1-negative tumors was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFκB family. These signatures were then verified in an independent series of hereditary and sporadic breast tumors, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes appears to be a common feature of ER-negative sporadic and hereditary breast cancer and is associated with good prognosis. Interestingly, the ESR1-negative tumors were sub-stratified into two groups presenting light differences in the magnitude of the expression of immune response transcripts and REL/NFκB transcription factors, and this could be dependent on the type of germline alteration. In addition, analysis of the human protein-protein interaction network provides the wiring diagram of critical molecular associations in BRCA1 tumorigenesis and identifies close relationships between the different signatures. Conclusions: In summary, in the present study we have established the gene expression profiling of a series of BRCA1 tumors and found that there is a further degree of heterogeneity beyond the main classification by the expression of ESR1 and the presence or absence of a basal-like phenotype. We have identified specific signatures for ESR1-positive and ESR1-negative BRCA1 tumors, the latter characterized by the enrichment of immune response and cell cycle genes, and have found that slight differences in the level of expression of the immune response stratify the ESR1-negative BRCA1 tumors into two additional sub-groups (A and B) with possible prognostic differences. NFkB could be a major driver responsible for the levels of both immune response and apoptotic genes in this group of tumors, which could in turn be related to the type of germline mutation in BRCA1. This study reveals the molecular complexity of BRCA1 breast tumors, which are found to display similarities to sporadic tumors, and suggests possible prognostic implications. 14 samples (primary breast tumors containing a BRCA1 mutation) were hybridized to a cDNA microarray in order to investigate the possible heterogeneity within the BRCA1 group.

Project description:BackgroundHeterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.MethodsWe performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.ResultsBased on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.ConclusionOur findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

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Gene and microRNA expression profiling of breast tumors from Chinese and Italian women [gene]

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