Presentation description

A novel 0.5 Mb locus containing the CNOT2 gene at chromosome 12q15 has been previously identified based on women with breast cancer whose tumors were extreme for PAM50-spectrum PC3, a gene expression metric. Tumors high for PC3 exhibit expression patterns with basal epithelial cells and estrogen/progesterone receptors. This intermediate phenotype of the Epithelial-Mesenchymal Transition (EMT) has been linked to the expression of basal cytokeratins. Additionally, high mammographic breast density (MBD) is a strong risk factor for breast cancer. Women with extremely dense breast tissue have a 1.8 to 6 times higher risk of breast cancer than similar-aged women with less dense breast tissue. MBD can be altered by exogenous hormones, which is key as it illustrates that interventions may exist to reduce risk. The GeoMx Digital Spatial Profiler (GeoMx DSP) is a new technology enabling spatial analysis of RNA in tissue specimens on slides. We will use this assay to identify if CNOT2 is the breast cancer susceptibility gene at the 12q15 locus and if germline variation in CNOT2 influences breast cancer risk via the EMT mechanism. We also hope to use this assay to identify molecular tumor characteristics associated with breast density. In addition to using the GeoMx Digital Spatial Profiler for our breast cancer projects, we will use this assay to expand the SPECTRA technique. SPECTRA is a statistical technique developed by the Camp Lab to characterize global gene expression (the transcriptome) by representing it as multiple quantitative tumor variables. We plan to expand the SPECTRA methodology to use data generated from the GeoMx Digital Spatial Profiler to explore gene-level and SPECTRA variable differences between normal and tumor breast tissue groups, and high-and-low-density breast tissue groups.