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Multi-omics Profiling of Asian Breast Cancers

ABSTRACT: Whole exome and transcriptome sequencing data of primary tumors from 178 Korean breast cancer patients.

PROVIDER: EGAS00001002621 | EGA |

REPOSITORIES: EGA

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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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Multi-omics Profiling of Asian Breast Cancers

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