Multi-omics Profiling of Asian Breast Cancers
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ABSTRACT:
PROVIDER: EGAS00001002621 | EGA |
REPOSITORIES: EGA
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Project description:Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-? signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.
| S-EPMC5928087 | biostudies-literature
Project description:We observed higher proportions of HER2+ and Luminal B but lower proportions of ER+ and Luminal A subtypes along with lower estrogen receptor (ER) expression in SMC compared to TCGA. Germline pathogenic mutations affecting BRCA1 or BRCA2 were found in 11% of SMC but only 5% of TCGA. TP53 was also more frequently mutated in SMC (48%) than in TCGA (32%).
2018-04-17 | GSE113184 | GEO
Project description:Multi-omics Profiling of Younger Asian Breast Cancers Reveals Distinctive Molecular Signatures
| PRJNA450393 | ENA
Project description:Abstract
The triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases. However, the prognosis and clinical outcomes of TNBC are worse than those of other BC subtypes due to a greater tumor and few therapeutically targetable oncogenic drivers. Numerous studies have employed genomic and transcriptomic approaches to identify clinically actionable TNBC subtypes in a comprehensive and unbiased manner using. While these analyses have advanced our knowledge of the molecular changes underlying TNBC, their clinical utility remains limited thus far. Given that proteins are the principal effector molecules of cellular signaling and function, we use a proteomic approach to quantitatively compare the abundances of 6,306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors to reveal actionable pathways for anti-cancer treatment. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. In addition, analyses of clinicopathological characteristics revealed associations between proteomic results and clinical phenotypes exhibited by each subtype. We validate the findings of our proteomics analysis, by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify representative in vitro models for each subtype. Collectively, our multi-omics data provide novel subtype-specific insights such as potential biomarkers, molecular drivers, and pharmacologic vulnerabilities for further investigations.
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Project description:Transcriptomic profiling of human breast tumors. Genomic and expression profiling using 38K BAC array-CGH and Illumina HT-12 beadchips were performed on 53 invasive breast tumors to assess the impact of gene dosage on gene expression patterns and the effect of other mechanisms on transcriptional levels. Array-CGH results was validated by FISH using tumors showing 8p11-p12 DNA amplification and expression profiling was confirmed using qPCR for 11 transcripts. Low-level gain, high-level gain/amplification, heterozygous loss and homozygous deletion (henceforth referred to as gain, amplification, loss and deletion) were defined as log2 ratio thresholds set at +0.2, >= +0.5, -0.2 and <=-1.0, respectively.
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Project description:Molecular Profiling of BRCA1-and BRCA2-associated Breast Cancers Identifies FGFR2 as a Gene More Highly Expressed in BRCA2-associated Tumors BRCA1- and BRCA2-associated tumors have many morphologic characteristics in common, but appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types, basal/myoepithelial and luminal, found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast cancer tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. Breast tumor RNAs from 7 germline BRCA1 and 6 germline BRCA2 carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction (RT-PCR) in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. Genes more highly expressed in BRCA1-associated tumors included stathmin/oncoprotein 18, osteopontin, TGFß2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. Genes more highly expressed in BRCA2-associated tumors had functions related to transcription, signal transduction (particularly MAPK signaling), cell proliferation, cell adhesion and extracellular matrix remodeling. BRCA2-associated cancers were characterized by the higher relative expression of amongst others, FGF1 and FGFR2. Tissue microarrays were used to validate the expression of FGFR2 protein by immunohistochemistry and Jagged 1 expression by in situ hybridization. BRCA2-associated cancers expressed higher levels of FGFR2 protein than BRCA1-associated cancers (p=0.004); whereas BRCA1-associated tumors exhibited elevated levels of Jagged1 mRNA compared to BRCA2-associated cancers (p=0.02). FGFR2 and FGF1 were more highly expressed in BRCA2-associated cancers compared with BRCA1-associated breast cancers, suggesting the existence of an autocrine or paracrine stimulatory loop. In addition to corroborating the basal-like signature of BRCA1-associated tumors, we identified osteopontin, stathmin/oncoprotein 18, TGFβ2, and Jagged 1 as being more highly expressed in BRCA1-associated tumors. Keywords: Gene expression profiling, genetic comparison
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