30 different fusions were detected in eight primary and ten refractory breast tumor samples, including recurrent rearrangements of phosphofructokinase (PFK) gene family (n=2) and protein kinase C (PRKC) gene family (n=4). 3.3.7.4 Notch pathway Ten different fusions were identified in three primary and six refractory samples. Functionally recurrent rearrangements of Notch gene families have been reported in breast cancer [39]. Three Notch gene fusions were identified in one primary and two refractory samples, of which fusion SEC22B:NOTCH2 was previously reported in a breast cell line [39]. In addition, recurrent rearrangements of corepressor interacting with RBPJ 1 (CIR1) have been identified in one primary sample (OSBPL6:CIR1) and one refractory samples (CERS6:CIR1). 3.3.7.5 TP53 pathway 26 different fusions were identified in twelve primary and nine refractory samples. Six recurrent rearrangements of PPM1D (n=5), THBS1 (n=3), PTEN (n=2), SESN1 (n=2), CCND1 (n=2) and CCNE1 (n=2) were detected. Protein phosphatase, Mg2+/Mn2+ dependent, 1D (PPM1D) dependent signalling has been reported as being “a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells” [114]. The cycling genes, including CCND1 and CCNE1, play an important role in cell cycle by activating cyclin-dependent kinase (CDK) [115]. 3.3.7.6 Estrogen pathway 28 different fusions were identified in ten primary and twelve refractory samples. Fusion ESR1:CCDC170 has been reported as recurrent rearrangements in endocrine-resistant luminal B tumors [40] and it was identified in three refractory and one primary sample. In addition, a novel fusion CDH8:ESR1 was detected in one refractory sample. The other recurrent fusion partners include ADCY8 (n=2), GNAI3 (n=2), ITPR2 (n=2) as well as SOS gene family (n=3), CREB gene family (n=3) and PLCB gene family (n=3). Guanine nucleotide-binding protein G(k) subunit alpha (GNAI3) can inhibit hepatocellular carcinoma cell migration and invasion [116]. Activation of cAMP response element-binding protein (CREB) is required to enhance aromatase expression in tamoxifen-resistant human breast cancer cells compared with control MCF-7 cells [117]. Phospholipase C (PLC) has six struc- ture isotypes such as 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta (PLCB). Interestingly, fusions of PLCB members were only detected in three refractory tumor samples. 3.3.7.7 Ras pathway 62 different fusions were detected in 33 samples, including recurrent rearrangements of fibroblast growth factor (FGF) gene family (n=5), Protein kinase (PRK) gene family (n=5), Phospholipases A2 (PLA2) gene family (n=3), RAPGEF5 (n=2), GNB1 (n=2), GNG12 (n=2), KITLG (n=2) and NF1 (n=4). Fibroblast growth factor 14 (FGF14), a member of fibroblast growth factor (FGF) gene family, is “an intracellular modulator of valtage-gated sodium channels” in central nervous system [118]. Rearrangements of FGF14 were only identified in three refractory tumors. In addition, rearrangements of FGF3, FGFR2 and FDF19 were detected in one refractory and two primary tumors, respectively. Guanine nucleotide binding protein (G Protein), beta polypeptide 1 (GNB1) can be regulated by phytoestrogens through estrogen receptor pathway in breast MCF-7 cells [119]. Guanine nucleotide binding protein (G Protein), gamma 12 (GNG12) can negatively regulate the inflam- matory response in the microglial cell line [120]. KIT-ligand (KITLG), also known as stem cell factor, can activate its receptor tyrosine kinase c-Kit, resulting in c-Kit’s autophosphorylation and initiation of signal transduction [121]. Fusions of KITLG were found in one primary and one refractory tumor (SH2D4A:KITLG). Neurofibromatosis type 1 (NF1) is associated with high risk of breast cancer development in women, especially at younger ages (< 50) [122]. Recurrent rearrangements of NF1 were identified in two primary and two refractory tumors. 3.3.7.8 ErbB pathway 50 different fusions were detected in 34 samples, including recurrent rearrangements of ERBB gene family (n=3), NRG gene family (n=4), PAK gene family (n=5), PTK2 (n=4) and GRB2 (n=3). Human epidermal growth factor receptor 2 (HER2) encoded by ERBB2 show overexpression in ∼20%-30% of breast cancer tumors [123]. It has been a drug target for HER2 positive breast cancer patients using Trastuzumab which is a HER2 receptor blocker [123]. Fusion ERBB2:ALG6 was found in one refractory tumor. Rearrangements of ERBB4 were detected in two primary tumors. Neuregulin 1 (NRG1), a ligand of HER3 receptor, may induce cancer stem cell like char- acteristics in breast cancer cell lines [124]. Lapatinib is a drug acting as an inhibitor of EGFR and HER2 [125]. A combination treatment using lapatinib and pertuzumab can induce tumor growth regression, which may overcome lapatinib-resistance due to NRG1-mediated signalling in HER2-amplified breast cancer [125]. Fusions ATP8A1:NRG1 and NRG1:MAK16 were identified in two primary samples. In addition, MLL5:NRG3 and SIN3A:NRG4 were found in two refractory samples. Growth factor receptor-bound protein 2 (GRB2) is one of the most significantly downreg- ulated genes in HER2 mutated breast cancer based on transcriptional analysis [126]. Fusion GRB2:TSEN54 was found in one refractory tumor; fusions GRB2:SEPT9 and GRB2:RNFT1 were identified in two primary tumors. Protein kinase C alpha (PRKCA) downregulates estrogen receptor expression by suppressing c-JUN phosphorylation in ER+breast cancer cells and may be a potential target to treat ER+ and tamoxifen-resistant breast cancer [127]. Fusions TMRM104:PRKCA and PRKCA:BEND5 were detected in two primary tumors and PRKCA:USP32 was in one refractory tumor. In addition, fusion PRKCB:ARFGEF2 was identified in one refractory tumor. PAK1 encodes serine/threonine protein kinase PAK1 and high level expression of PAK1 is associated with poor clinical outcomes in luminal breast cancer [128]. Rearrangements of PAK1 have been identified in one refractory and three primary samples. In addition, fusion JAG1:PAK7 was detected in one primary sample. Protein tyrosine kinase 2 (PTK2) is a focal adhesion-associated protein kinase (FAK) which plays an important role in regulation of cellular responses such as cell adhesion, migration and survival [129]. Interestingly, different fusions of PTK2 have been only detected in four primary tumors. A Her2 breast cancer pathway analysis based on INGENUITY is given in Figure 3.25. 3.3.7.9 PI3K-AKT-mTOR pathway 87 different fusions were detected in 50 samples, including recurrent rearrangements of collagen (COL) gene family (n=7), integrin (ITG) gene family (n=9), MAMA4 (n=2), RPTOR (n=2) and Figure 3.25: Fusion-involved genes in Her2 breast cancer pathway based on INGENUITY RPS6KB1 (n=5). Ribosomal protein S6 kinase beta-1 (RPS6KB1), encoding the 70kDa ribosomal protein S6 kinase (p70S6K), is involved in various human diseases and it performs as “a biomarker for response to immunosuppressant as well as anticancer effects of inhibitors of the mTOR” [130]. RPS6KB1 activates ESR1 by phosphorylating ESR1 on serine 167, which is a key position, leading to ESR1 mediated cell proliferation in breast cancer [131]. Interaction between tamoxifen and RPS6KB1 has been identified and phosphorylated RPS6KB1 significantly associated with tamoxifen resistance [132]. Rearrangements of RPS6KB1 were identified in two primary and three refractory tumors. In addition, fusion of RPS6KA1 was found in one primary tumor. 3.3.7.10 MAPK pathway 69 different fusions were detected in 42 samples, including recurrent rearrangements of calcium- channels voltage-dependent (CACN) gene family (n=5), dual specificity protein phosphatase (DUSP) gene family (n=2), mitogen-activated protein kinase (MAPK) related genes (n=10) and serine/threonine-protein kinase TAO (TAOK) gene family (n=5). Mitogen-activated protein kinases (MAPKs) consist of different protein-serine/threonine kinases, which play important roles in signal transduction pathways that regulate cell functions such as proliferation and apoptosis [133]. Rearrangements of MAPK related genes were identified in one refractory and nine primary tumors. The MAPK pathway analysis based on INGENUITY is shown in Figure 3.26. In document Indicadores claves de rendimiento (Key performance indicators – KPIS) en el servicio de emergencias de adultos del Hospital Carlos Andrade Marín en el mes de enero de 2018 (página 37-41)
