Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
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PROVIDER: PRJNA445760 | ENA |
REPOSITORIES: ENA
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Project description:Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
| PRJNA445762 | ENA
Project description:Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts. No pathogenic mutations were identified in SPRED1 A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in NF1 was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering TP53, BRCA1, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in NF1 likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1.
| S-EPMC5880258 | biostudies-literature
Project description:<p>Targeted genetic sequencing was performed on a 41-year-old female with metaplastic breast cancer (MBC) and neurofibromatosis type I (NF1). A custom panel capturing 279 cancer related genes was used to identify a germline pathogenic SNV in NF1, as well several other somatic alterations. </p>
| phs001566 | dbGaP
Project description:We previously discovered a sex-by-genotype defect in microglia function using a germline heterozygous knockout mouse model of Neurofibromatosis type 1 (Nf1+/- mice), in which only microglia from male Nf1+/- mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1+/- microglia exhibit differences in protein expression, which largely reflect pathways involved cytoskeletal organization. In keeping with potential defects in cytoskeletal function, only male Nf1+/- microglia had reduced process arborization and surveillance capacity. Next, to determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG+/- mice). Surprisingly, neither male nor female Nf1MG+/- mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP+/- mice), the microglia defects found in Nf1+/- mice were recapitulated. Collectively, these data reveal that Nf1+/- sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.
2023-05-10 | PXD035881 | Pride
Project description:Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. The intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear. Herein, 59 NST components and paired metaplastic components (spindle sarcomatous [SPS], matrix-producing, rhabdomyoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling. Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial–mesenchymal transition, and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlap in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. The EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis. In summary, we presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs.
2023-01-31 | GSE212245 | GEO
Project description:CGH arrays for Smukowski Heil, et al MBE 2017. Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we address these questions using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae x Saccharomyces uvarum and their parentals. We evolved these strains in nutrient limited conditions for hundreds of generations and sequenced the resulting cultures to identify genomic changes. Analysis of 16 hybrid clones and 16 parental clones identified numerous point mutations, copy number changes, and loss of heterozygosity events, including species biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated loss of heterozygosity at the high affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the loss of heterozygosity is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity, and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation.
2017-02-21 | GSE95086 | GEO
Project description:SNP6 profiling of metaplastic breast carcinoma Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer, preferentially displaying a triple-negative phenotype (i.e. lacking estrogen receptor, progesterone receptor and HER2 expression). We sought to define the transcriptomic heterogeneity of MBCs on the basis of current gene expression microarray-based classifiers and to determine whether MBCs display gene copy number profiles consistent with those of BRCA1-associated breast cancers.
2014-10-31 | E-GEOD-57548 | biostudies-arrayexpress
Project description:Genes involved in tumorigenesis associated with neurofibromatosis type 1.
2007-01-12 | E-TABM-69 | biostudies-arrayexpress
Project description:SNP6 profiling of metaplastic breast carcinoma
2014-10-31 | GSE57548 | GEO
Project description:Breast cancer cells and two metaplastic breast cancer cell lines were used: a widely available, HS578T, and a novel line isolated from a metaplastic breast cancer tumor, BAS. Doxorubicin and paclitaxel resistant derivatives of these metaplastic lines were generated and miR profiling performed.
2023-01-29 | GSE144445 | GEO