Genes with copy number gains observed in more than half of breast cancer patients
First, I identified genes with copy number gain events (CNV gain) observed in more than 50% of breast cancer patients (n = 1058), using CNV (copy number variation) data from Genomic Data Commons (GDC) Data Portal (Figure 1). I found that there are 49 genes with copy number gain events observed in more than half of the patients with breast cancer (Figure 1). I ordered genes from highest to lowest CNV gain percentage in Figure 1. Gene with the highest CNV gain percentage (74.1%) in breast cancer patients is MDM4, followed by SLC45A3 (73.44%) and ELK4 (73.35%) (Figure 1). From this list of genes, I only selected genes indicated by red columns in Figure 1 (namely, SLC45A3, RGS7, FCRL4, CSMD4, FAM135B and TRAF7) for further analysis based on two criteria: (1) the expression of the gene is increased in breast tumors compared to healthy breast tissue (see below), and (2) there are maximum 4 papers in PubMed for the gene in the context of breast cancer, so it is largely understudied in breast cancer research. I analyzed the expression of these 6 selected genes in terms of ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2; ERBB2) expression in breast cancer patients.
SLC45A3 expression is lower in breast cancer patients with ER-positive or PR-positive status
Initially, I found that SLC45A3 (Solute Carrier Family 45 Member 3) expression is higher in breast tumors compared to normal breast tissue (p = 0.026, our first criteria, Figure 2A). Next, I showed that SLC45A3 expression is lower in ER (estrogen receptor)-positive (p < 2e-16) and PR (progesterone receptor)-positive (p = 2.5e-12) breast cancer patients compared to those with ER-negative and PR-negative tumors, respectively (Figure 2B, 2C). However, there is no difference in SLC45A3 transcript levels between HER2-negative and HER-positive breast cancer patients (p = 0.75, Figure 2D). I also observed that breast cancer patients with triple negative status (ER-, PR-, HER2-; “- - -”) have the highest mean expression of SLC45A3 (Figure 2E).
RGS7 expression is higher in breast cancer patients with ER-positive or PR-positive status
The percentage of breast cancer patients with RGS7 (Regulator Of G Protein Signaling 7) copy number gains (CNV gain) is around 70% (Figure 1). I found that RGS7 transcript levels are higher in breast tumors than normal breast tissue (p = 2.1e-05, Figure 3A). RGS7 expression is higher in breast tumors with ER-positive (p = 1.6e-09) or PR-positive status (p = 1.4e-09) compared to those with ER-negative or PR-negative status, respectively (Figure 3B, 3C). In contrast, RGS7 mRNA levels are lower in breast tumors with HER2+ status than HER2- status (p = 0.018) (Figure 3D). I also showed that among all receptor status combinations, breast tumors with ER+, PR+ and HER2- status (“+ + -”) have the highest RGS7 expression (Figure 3E).
FCRL4 expression is lower in breast tumors with ER-positive or PR-positive status
After showing that the percentage of breast cancer patients with FCRL4 (Fc Receptor Like 4) copy number gains is around 68% (Figure 1), and that the expression of FCRL4 is higher in breast tumors than non-malignant breast tissue (p = 2.4e-12, Figure 4A), I found that FCRL4 transcript levels are lower in breast tumors with ER-positive (p = 1.9e-06) or PR-positive status (p = 0.0025) than those with ER-negative or PR-negative status, respectively (Figure 4B, 4C). However, FCRL4 expression does not significantly change depending on HER2 status in breast tumors (p =0.63; Figure 4D). FCRL4 expression based on ER, PR and HER2 status combinations is shown in Figure 4E.
CSMD3 transcript levels are lower in breast tumors with HER2-positive status
I found that the percentage of breast cancer patients with CSMD3 (CUB And Sushi Multiple Domains 3) copy number gains is around 57% (Figure 1), and that the expression of CSMD3 is higher in breast tumors compared to healthy breast tissue (p = 0.025, Figure 5A). Then, I showed that CSMD3 mRNA levels do not change depending on either ER or PR status in breast tumors (p = 0.18 and 0.53, respectively) (Figure 5B, 5C). However, I observed that CSMD3 expression is lower in HER2+ breast tumors than HER2- breast tumors (p = 0.0011; Figure 5D). In addition, CSMD3 expression is higher in ER+,PR+,HER2- breast tumors compared to those with triple positive status (TNBC) (p = 0.0069; Figure 5E).
FAM135B expression is higher in breast cancer patients with ER-positive or PR-positive status but lower in those with HER2-positive status
After showing that the percentage of breast cancer patients with FAM135B (Family With Sequence Similarity 135 Member B) copy number gains is around 53% (Figure 1), and that FAM135B mRNA levels are higher in breast tumors than non-malignant breast tissue (p = 0.019; Figure 6A), I found that FAM135B transcript levels are higher in breast cancer patients with ER-positive (p < 2e-16) or PR-positive status (p < 2e-16) compared to those with ER-positive or PR-positive status, respectively (Figure 6B, 6C); but, lower in those with HER2-positive status than those with HER2-negative status (p = 0.0028) (Figure 6D). As expected, FAM135B expression is the highest in ER+, PR+, HER2- breast tumors (Figure 6E).
TRAF7 expression does not change depending on ER, PR and HER2 status in breast tumors
I first showed that the percentage of patients with breast cancer who have TRAF7 (TNF Receptor Associated Factor 7) copy number gains is 50% (Figure 1), and that TRAF7 transcript levels are higher in breast tumors compared to healthy breast tissue (p < 2e-16, Figure 7A). However, I observed that TRAF7 transcript levels do not change depending on ER, PR and HER2 status in tumors from breast cancer patients (p = 0.1, 0.48 and 0.87, respectively) (Figure 7B, 7C, 7D). Therefore, there is no significant difference in TRAF7 expression between different combinations of these three receptors’ status in breast tumors (Figure 7E).