FusionPlex Solid Tumor Kit

The Archer® FusionPlex® Solid Tumor Kit is a robust targeted sequencing assay to simultaneously detect and identify Fusions and other Mutations associated with over 50 genes linked to various carcinomas. Also included in the kit are primers that target known sarcoma- and hematological malignancy-associated Fusions as well as prominent BRAF and PDGFA Mutations. The power of the FusionPlex Solid Tumor Kit lies in Archer’s proprietary Anchored Multiplex PCR™-based enrichment. This chemistry enables detection of all Fusions associated with the genes in this kit in a single sequencing assay, even without prior knowledge of Fusion partners or breakpoints.
For Research Use Only. Not for use in diagnostic procedures.


  • Comprehensive - identify carcinoma-related Fusions in a single assay
  • Detailed - characterize Fusion partners at single-nucleotide resolution
  • Streamlined – reduce turn-around time and eliminate reflex testing
  • Flexible – works with all clinical sample types, including FFPE

Product Details

Assay Targets (click to see target details)

Target details (click to learn more about the gene)

AKT3 NM_005465 1, 2, 3 5' Fusion
ALK NM_004304 19, (intron19), 20, 21, 22 5' Fusion
ARHGAP26 NM_015071 2, 10, 11, 12 5' Fusion
AXL NM_021913 19, 20 3' Fusion
BRAF NM_004333 7, 8 3' Fusion
BRAF NM_004333 7, 8, 9, 10, 11, 12 5' Fusion
BRAF NM_004333 15 5' Fusion
BRAF NM_004333 V600E n/a Mutation
BRD3 NM_007371 9, 10, 11, 12 3' Fusion
BRD4 NM_014299 10, 11 3' Fusion
EGFR NM_005228 7, 9, 16, 20 5' Fusion
EGFR NM_005228 8 (2-7 exon skipping event) n/a Mutation
EGFR NM_005228 24, 25 3' Fusion
ERG NM_004449 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 5' Fusion
ESR1 NM_001122742 3, 4, 5, 6 3' Fusion
ETV1 NM_004956 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 5' Fusion
ETV4 NM_001986 2, 4, 5, 6, 7, 8, 9, 10 5' Fusion
ETV5 NM_004454 2, 3, 7, 8, 9 5' Fusion
ETV6 NM_001987 1, 2, 3, 4, 5, 6 3' Fusion
ETV6 NM_001987 2, 3, 5, 6, 7 5' Fusion
EWSR1 NM_005243 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 3' Fusion
FGFR1 NM_015850 2, 8, 9, 10, 17 5' Fusion
FGFR2 NM_000141 2, 8, 9, 10 5' Fusion
FGFR2 NM_000141 17 3' Fusion
FGFR3 NM_000142 17, Intron 17 3' Fusion
FGFR3 NM_000142 8, 9, 10 5' Fusion
FGR NM_005248 2 5' Fusion
INSR NM_000208 20, 21, 22 3' Fusion
INSR NM_000208 12, 13, 14, 15, 16, 17, 18, 19 5' Fusion
MAML2 NM_032427 2, 3 5' Fusion
MAST1 NM_014975 7, 8, 9, 18, 19, 20, 21 5' Fusion
MAST2 NM_015112 2, 3, 5, 6 5' Fusion
MET NM_000245 13 3' Fusion
MET NM_000245 13, 15 (exon 14 skipping event) n/a Mutation
MSMB NM_002443 2, 3, 4 3' Fusion
MUSK NM_005592 7, 8, 9, 11, 12, 13, 14 5' Fusion
MYB NM_001130173 7, 8, 9, 11, 12, 13, 14, 15, 16 3' Fusion
NOTCH1 NM_017617 2, 4, 29, 30, 31 3' Fusion
NOTCH1 NM_017617 26, 27, 28, 29 (internal exon 3-27 deletion) 5' Fusion
NOTCH2 NM_024408 5, 6, 7 3' Fusion
NOTCH2 NM_024408 26, 27, 28 5' Fusion
NRG1 NM_004495 1, 2, 3, 6 5' Fusion
NTRK1 NM_002529 8, 10, 11, 12, 13 5' Fusion
NTRK2 NM_006180 11, 12, 13, 14, 15, 16, 17 5' Fusion
NTRK3 NM_002530 13, 14, 15, 16 5' Fusion
NTRK3 NM_001007156 15 5' Fusion
NUMBL NM_004756 3 5' Fusion
NUTM1 NM_175741 3 5' Fusion
PDGFRA NM_006206 7 (exon 8 deletion) n/a Mutation
PDGFRA NM_006206 10, 11, 12, 13, 14, 5' Fusion
PDGFRA NM_006206 T674I, D842V n/a Mutation
PDGFRB NM_002609 8, 9, 10, 11, 12, 13, 14 5' Fusion
PIK3CA NM_006218 2 5' Fusion
PKN1 NM_002741 10, 11, 12, 13 5' Fusion
PPARG NM_015869 1, 2, 3 5' Fusion
PRKCA NM_002737 4, 5, 6 5' Fusion
PRKCB NM_002738 3 5' Fusion
RAF1 NM_002880 4, 5, 6, 7, 9 3' Fusion
RAF1 NM_002880 4, 5, 6, 7, 9, 10, 11, 12 5' Fusion
RELA NM_021975 3, 4 5' Fusion
RET NM_020630 8, 9, 10, 11, 12, 13 5' Fusion
ROS1 NM_002944 31, 32, 33, 34, 35, 36, 37 5' Fusion
RSPO2 NM_178565 1, 2 5' Fusion
RSPO3 NM_032784 2 5' Fusion
TERT NM_198253 2 5' Fusion
TFE3 NM_006521 2, 3, 4, 5, 6 3' Fusion
TFE3 NM_006521 2, 3, 4, 5, 6, 7, 8 5' Fusion
TFEB NM_007162 1, 2 5' Fusion
THADA NM_022065 28 3' Fusion
TMPRSS2 NM_005656 1, 2, 3, 4, 5, 6 3' Fusion
TMPRSS2 NM_001135099 1 3' Fusion



What is carcinoma?

Carcinoma is a vast cancer type that arises from epithelial cells, which line the cavities of the body. These cells are tightly packed into epithelial sheets and anchored by a basement membrane to provide a high tensile-strength protective barrier for organs. Secretory epithelial cells also aid in organ function, such as goblet cells that maintain the lumenal mucus layer in the intestines and parietal cells that secrete acid into the stomach (1).

Carcinomas form due to uncontrolled growth of epithelial cells. Benign tumors remain localized to the initial site of neoplastic growth but can progress to metastatic disease, characterized by an invasive phenotype that enables the tumor cells to spread to distant sites in the body.

Gene fusions play a key role in carcinogenesis. Many of the driver mutations are in genes that express kinases, as indicated in the tables above. Fusions in these genes often unlink the kinase domains of the proteins from regulatory subunits, resulting in constitutive activation of the kinase function (6, 52).

Carcinoma types

Epithelial cells are widely found in the body, and thus carcinomas can arise from many sites, as shown in the table below (1).

Sites where carcinomas can arise
Prostate Liver Gall bladder
Mammary gland Lung Skin
Ovary Urinary bladder Gastrointestinal tract (e.g., mouth, throat, stomach, small and large intestine)

Carcinomas are categorized based on function; neoplasms that arise from protective epithelial cells are classified as squamous cell carcinomas, while those that arise from secretory epithelial cells are adenocarcinomas. And while some organs can yield only squamous cell carcinomas or adenocarcinomas, both types can arise from a given organ because of the often mosaic nature of the epithelium (1).

Carcinoma incidence and mortality

Life-threatening carcinomas make up over 80% of all cancers. In the United States, prostate cancer followed by female breast cancer having the highest incidence rates, while lung cancer by far has the highest mortality rate

US cancer incidence and mortality rates by site, 2007-2011

Carcinomas comprise the majority of US cancer incidence and mortality rates (2).

Limitations to current translocation detection techniques

Chromosomal translocations have been traditionally detected using methods that vary in sensitivity, scalability and the ability to multiplex. These methods include:

  • Fluorescence in situ hybridization (FISH)
  • Immunohistochemistry (IHC)
  • Reverse transcription polymerase chain reaction (RT-PCR)

IHC is a relatively straightforward method to detect proteins in fixed tissue sections using antibodies specific to the target protein. IHC can indirectly detect translocations if the gene fusion leads to overexpression of a fusion protein above background levels, with the intensity of the staining indicative of fusion protein expression level. Although not technically challenging, a key limitation to IHC as an effective translocation detection strategy is the need for antibodies that target one of the fusion partners. Also, IHC only provides a qualitative analysis because of the nonlinear chromogenic signal, and the limited number of chromogenic signals available prevents the use of IHC for multiplexing.

FISH relies on a fluorescent DNA probe that hybridizes to the target gene in chromosomal DNA, and translocations are often detected by visually determining the colocalization of two fluorescent probes that hybridize to flanking sequences in the target fusion event. FISH is more objective than IHC, because colocalization of the two fluorescent probes is positive for the fusion event. But there is some subjectivity because of the level of colocalization, especially when the two genes are normally in close proximity. FISH is also technically challenging, laborious by both the preparation and preview, poorly scalable and limited in multiplexing.

RT-PCR is an inexpensive and robust method to detect gene fusions using very low input amounts by reverse transcribing messenger RNA into complementary DNA (cDNA) and then amplifying and detecting the target genes. The method yields a relatively straightforward yes-or-no readout, but the sequences of both fusion partners must be known to craft forward and reverse primers to amplify the fusion sequence. RT-PCR also is limited in scalability and clinical sensitivity.

Gene fusions can be detected by histological and molecular methods, including IHC, FISH and RT-PCR (from left to right).

Gene fusions can be detected by histological and molecular methods, including IHC, FISH and RT-PCR (from left to right)

Because of limitations associated with these traditional methods, cutting-edge technologies are increasingly defining novel cancer subtypes through the identification of new chromosomal translocations (3-5).

Detecting fusions using the Archer FusionPlex Solid Tumor Kit

ArcherDX has developed a kit for the rapid detection of solid tumor-associated translocations from total nucleic acid isolated from tumor samples—including FFPE-preserved specimens. Anchored Multiplex PCR (AMP) enables rapid preparation of target-enriched libraries to detect and characterize gene rearrangements by next-generation sequencing. The Archer technology permits the simultaneous detection of both known recurrent fusions as well as previously unidentified fusions at key breakpoints in target genes. The FusionPlex Solid Tumor Kit offers a complete fusion detection solution, from library preparation through data analysis, for both the Illumina and Ion Torrent platforms.



Solid tumor-associated fusion genes and other mutations


AKT3 (v-akt murine thymoma viral oncogene homolog 3) is located at chromosome 1q44 and encodes AKT3, a 479-amino acid protein that is a member of the serine/threonine kinase protein kinase B (PKB) family. The AKT3 signaling pathway plays a critical role in melanoma formation and invasion and is thus an attractive target for the treatment of malignant melanoma.


The gene encodes a 22-kDa protein that is a receptor tyrosine kinase that is a member of the classical insulin superfamily. Although the actual physiological function of ALK is uncertain, studies have shown that pleiotrophin and midkine are activating ligands. ALK is activated by dimerization and autophosphoyrlation in trans, resulting in the activation of downstream targets. ALK has 22 known fusion partners, with the partners regulating expression and localization and the conserved ALK kinase domain controlling ALK activity (6).

ALK was first discovered in NSCLC in 2007 as a fusion with echinoderm microtubule-associated protein-like 4 (EML4), and multiple EML4-ALK fusion variants have since been discovered that modify protein size, frequency in NSCLC and sensitivity to inhibitors (7-9). While multiple driver mutations can occur in a single cancer incidence, ALK rearrangements are almost always mutually exclusive and occur in 3-5% of patients with lung cancer.


ARHGAP26 encodes a GTPase-activating protein that binds to focal adhesion kinase (FAK) and mediates the activity of RhoA and Cdc42 GTPases. RhoA-mediated signaling links plasma membrane receptors to focal adhesion and actin stress fiber assembly (10). Given its regulatory properties in the endocytic pathway, cell spreading and muscle development, ARHGAP26 plays an integral role the phenotypic transformation of cell as it becomes cancerous.

ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding (11). Sequencing results have revealed fusion transcripts in which ARHGAP26 activates a cryptic splice site within exon 5 of CLDN18, yielding an in-frame fusion predicted to maintain the transmembrane domains of CLDN18 while fusing a large segment of ARHGAP26 to the cytoplasmic carboxy terminus of CLDN18. This oncoprotein retains its carboxy-terminal GAP domain of ARHGAP26/6, potentially affecting RhoA activity and cell motility (12).


The AXL gene encodes the receptor tyrosine kinase UFO, which is responsible for regulating cell survival, cell proliferation, migration and differentiation via binding to the growth factor GAS6. Once activated, multiple subunits of PI3-kinase are phosphorylated, as are GRB2, PLCG1, LCK, PTPN11 and other potential candidates. GRB2 recruitment leads to the downstream activation of AKT (13). The fusion AXL–MBIP carries protein tyrosine kinase domains and dimerization units that are essential to activate chimeric tyrosine kinases (14).


BRAF is the most potent activator of the mitogen-activated kinase (MAPK) extracellular-regulated kinase (ERK). Mutations in this gene are associated with multiple types of cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma and lung adenocarcinoma (15). Mutations in the RAS/BRAF/MEK/ERK pathway occur in approximately 30% of all cancers, with BRAF mutations in approximately 7% of cancers. Of these BRAF mutations, 90% are characterized by a thymine-to-adenine single-base change at position 1799 that leads to a glutamine-for-valine substitution in exon 15 at residue 600 (V600E). BRAFV600E is a 500-fold gain-of-function mutation leading to constitutive activation of MEK/ERK signaling (16).

A recent genomic profiling of spindle cell neoplasm from a cancer patient identified the KIAA1549-BRAF gene fusion, the result of the combinatorial effects of a tandem duplication event, a homozygous deletion of PTEN and frameshift insertions/deletions in CDKN2A A68fs*51, SUFU E283fs*3 and MAP3K1 N325fs*3. This neoplasm was responsive to a combination therapy of sorafenib, temsirolimus and bevazicumab, exhibiting a 25% reduction in tumor volume (17).


This gene encodes a cell surface receptor that is a member of the epidermal growth factor receptor (EGFR) family and binds to epidermal growth factor. Ligand binding induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation (18). The EGFR-SEPT14 fusion has recently been shown to underlie glioblastomas (GBM), the most common primary intrinsic malignant brain tumor that affects ~10, 000 new patients each year and has a median survival rate of 12–15 months. EGFR-SEPT14 fusions activate STAT3 signaling, leading to ligand-independent cell division and sensitivity to EGFR inhibition. These findings highlight new potential therapeutic targets (19).


ERG (ETS-related gene) encodes one of the erythroblast transformation-specific (ETS) transcriptions factors and regulates embryonic development, cell proliferation, differentiation, angiogenesis, inflammation and apoptosis (20). ERG and other ETS-related fusions have frequently been identified in prostate cancers, the most frequent being TMPRSS2-ERG, which is estimated in a genomic profiling study to be present in 47% of prostatic small cell carcinomas (21). Other ERG fusion partners found in prostate cancer include SLC45A3 and NDRG1 (22). EWSR1-ERG fusions have also been found in Ewing’s sarcoma (23).


This gene encodes estrogen receptor (ER), a ligand-activated transcription factor. Estrogen and its ligands have key roles in sexual development, reproductive function and roles in other tissues. Estrogen receptors are also oncogenic (24). Characterizing estrogen receptor-positive (ER+) breast cancers is important because it can determine prognosis and treatment paradigms. A more aggressive subset of ER+ breast cancer has been shown to harbor the ESR1-CCDC170 gene rearrangement; CCDC170 encodes a protein with unknown function (25).

ETV1, 4, 5

Erythroblast transformation-specific transcription factors (ETS family) include ETV1, ETV4, and ETV5, which regulate many target genes that modulate biological processes such as migration, angiogenesis, proliferation, cell growth and differentiation. Besides the EWS-ETV1 fusion resulting from a t(7;22)(p22;q12) translocation in Erwing sarcoma (27), ETS family fusions are prevalent in prostate cancers and have at least 14 unique 5’ fusion partners (28, 29). Most likely, these fusion partners can be rearranged with any of the other ETS genes (29). In each case, fusion transcripts lead to overexpression of N-truncated ETS proteins or chimeric fusion proteins (28, 30).


THE ETV6 gene located at 12p13 encodes a protein containing a helix-loop-helix (HLH) domain and an ETS domain. ETV6 acts as a powerful transcriptional repressor and plays a crucial role in embryonic development and hematopoietic regulation. ETV6 fusions are implicated in leukemia, mylodysplastic syndromes (MDS) and sarcoma through 33 different fusion partners. There are 8 exons in ETV6, and fusions can occur between any of the exons with varying effects and implications.


Ewing sarcoma breakpoint region 1 (EWSR1) is aptly named for its susceptibility for breakage and translocation in soft-tissue tumors, notably Ewing’s sarcoma. Located on 22q12.2, EWSR1 spans 40kb with 17 exons and encodes for the ubiquitously expressed EWS protein involved in transcriptional regulation and initiation and mRNA splicing (31). EWSR1 can translocate with a variety of partners but typically with those encoding transcriptional regulators. The chimeric proteins interfere with molecular pathways crucial for cell differentiation, proliferation and growth and often are responsible for oncogenesis in sarcomas.

FGFR1, 2, 3

Fibroblast growth factor receptors are a family of tyrosine kinase receptors involved in proliferation, anti-apoptosis, drug resistance and angiogenesis. In glioblastoma multiforme, FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively (32). FGFR2 fusions have only recently been discovered but have been found in a variety of different cancer types. Learn more about the FGFR-specific FusionPlex Kit.


Intraosseous salivary gland carcinomas are rare and make up only 2% to 3% of reported mucoepidermoid carcinomas (33). The MECT1-MAML2 translocation underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from MECT1, which has an unknown function, with exons 2-5 of the transcription factor MAML2. Cloning experiments have identified that this fusion is a mechanism for disrupting Notch signaling in human tumorigenesis by activating HES1 transcription independently of both Notch ligand and nuclear effector CSL binding (34).


The roles of MAST kinases and somatic mutations have not been fully characterized; however, MAST1 and MAST2 gene fusions have been demonstrated to drive proliferation in breast epithelial cells. In addition, three independent cases of MAST gene fusions have been recently identified by transcriptome analyses: ARID1A-MAST2, ZNF700-MAST1 and NFIX-MAST1. This work demonstrates the power of RNA-seq in identifying rare and targetable mutations (35).


MET expresses the c-MET receptor tyrosine kinase, which is involved in tumorigenesis and progression to metastatic disease via increased cell motility and invasion. The c-Met receptor has been implicated in various solid tumors, including small cell lung cancer, renal papillary and gastrointestinal cancer. Somatic mutations leading to alternative splicing in the juxtamembrane domain is thought to play a mechanistic role in modulating c-MET signaling. Multiple 8-kb MET mRNA variants have been reported. One variant is caused by a 2-bp insertion in the pre-juxtamembrane domain (intron 13), skipping the entire juxtamembrane domain (exon 14) of MET (36). Cells expressing this exon skipping variant exhibit enhanced ligand-mediated proliferation and significant in vivo tumor growth (37).


Microseminoprotein beta (MSMB) is a member of the immunoglobulin binding factor family and is expressed by epithelial cells in the prostate gland (38). The fusion MSMB-NCOA4 retains all functional elements of NCOA4 protein; NCOA4 is a co-activator of the androgen receptor. It is not uncommon for prostate cancers to be highly dependent on androgen receptor function. As such, it has been hypothesized that MSMB-NCOA4 may play functional roles in cancer (39).


The transcription factor MYB plays a role in hematopoiesis regulation (40). It was identified as an oncogene related to leukemias due to a rearrangement at 6q23 upstream of the coding region (41). Additionally, MYB-NFIB chimeric fusion transcripts are predominantly associated with adenoid cystic carcinomas of the breast, head and neck (42).


Notch family members regulate interactions between physically adjacent cells and play a role in a variety of developmental processes by controlling cell fate decisions (43). Breast cancer cell lines known to be positive for Notch gene rearrangements are sensitive to inhibition of Notch signaling (35). These findings show another example of a subset of carcinomas being driven by genomic rearrangements and further suggest that targeting sequencing could identify biomarkers for therapeutic targets.


Neuregulin 1 (NRG1) is a ligand for the ERBB3 and ERBB4 tyrosine kinase receptors. During ligand-receptor binding, the co-receptors ERBB1 and ERBB2 are simultaneously recruited, resulting in tyrosine phosphorylation and receptor activation (44). A recent study examining the known proto-oncogene KRAS reported that the oncogenic fusions CD74-NRG1 and SLC3A2-NRG1 occurred independently of KRAS mutations at a rate of 17.6%. Furthermore, clinically approved tyrosine kinase inhibitors suppressed NIH3T3 cells expressing these fusions (45). These findings suggest that NRG1 fusions might present robust clinical biomarkers.

NTRK1, 2, 3

Neurotrophic tyrosine kinases are a family of tyrosine kinase receptors involved in nervous system development. Fusions associated with these proteins are found in a variety of different solid tumors. TP53-NTRK1 and ETV6-NTRK3 fusions are both found in multiple tumor types. Learn more about the NTRK-specific FusionPlex Kit.


Nuclear protein of the testis (NUT) Midline Carcinoma family member 1 (NUTM1) translocations at 15q14 characterize an aggressive subtype of squamous cell carcinomas known as NUT midline carcinomas (NMC) (46). The majority of NMC’s harbor fusion proteins between NUTM1 and the BET family genes BRD4 and BRD3 that inhibit differentiation and maintain proliferation. However, approximately 20% of NMCs include NUT being fused to uncharacterized, non-BRD genes, including NSD3-NUT (47). While NMC is very resistant to standard chemotherapy, molecular-based targeted therapies like histone deacetylase inhibitors (HDACi) and bromodomain inhibitors (BETi) might help hinder tumor growth (48).


Platelet-derived growth factor receptor alpha (PDGFRA) encodes a PDGF-family cell surface tyrosine kinase receptor. PDGFR activation results in increased cellular proliferation, migration and angiogenesis. Translocations can cause the intracellular domains of PDGFRα and PDGFβ to fuse to various gene partners, which, in combination with the loss of regulatory sequences in the transmembrane and juxtamembrane domains, leads to constitutive activation of the receptor kinases (49).

This mechanism of action has been shown to be the pathogenesis of PDGFRA/B fusion-derived myeloproliferative neoplasms like chronic myeloid leukemia (CML) and chronic eosinophilic leukemia. The FIP1L1-PDGFRA fusion associated with chronic eosinophilic leukemia, the ETV6-PDGFRB fusion common in CML, and fusions involving the 25 other reported fusion partners of PDGFRA and PDGFRA/B are very sensitive to imatinib (50).

However, there is a point mutation within the kinase domain of FIP1L1- PDGFRa (T6741) that results in resistance to imatinib and conventional treatment, resulting in a dismal prognosis. There is evidence that sorafenib treatment would be beneficial in these circumstances, except in instances where another point mutation (D842V) is present (51).


Phosphatidylinositol-4, 5-biosphosphate 3-kinase, catalytic subunit alpha (PIK3CA) is a tyrosine kinase oncogene that is susceptible to fusions in a variety of cancers. Exon 1 of TBLXR1 can fuse to exon 2 of PIK3CA in breast cancer and prostate cancer, and exon 3 of FNDC3B can fuse to the 5’UTR in uterine corpus endometrial carcinoma cases (52). In the TBL1XR1-PIK3CA fusion, the PIK3CA coding sequence is intact and the mRNA is overexpressed—suggestive of a promoter fusion. This mechanism of action could potentially be targeted with expanded use of targeted therapies such as PI3K, AKT or mTOR inhibitors (52)


Protein kinase N1 (PKN1) is a gatekeeper of androgen receptor-dependent transcription and is implicated in androgen receptor-induced tumor cell proliferation (53). PKN1 fusions have been discovered in squamous cell lung carcinoma and hepatocellular carcinoma. Two fusions – ANXA4-PKN1 and TECR-PKN1 – result in the deletion of the regulatory N-terminal domain and could lead to constitutive activation of the kinase (52).


Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear hormone receptor and master regulator of adipocyte differentiation. The chromosomal translocation t(2;3)(q13;p25) results in a fusion between PAX3 and PPARG that is implicated to be the driver mutation in 35% of follicular thyroid carcinomas (54). The gene fusion results in the production of a Pax8-PPARG fusion protein (PPFP). The specific mechanisms of PPFP as an oncoprotein remains to be defined, yet it is considered to act as a dominant-negative inhibitor of wildtype PPARG or a unique transcriptional activator to subsets of PPARG- and PAX8-responsive genes. PPARG agonist pioglitazone has been shown to have therapeutic implications on PPFP-positive thyroid carcinoma (55).


Protein kinase C, alpha and beta (PRKCA and PRKCB) fusions have recently been described in a variety of malignancies. A recurrent translocation, t(9;17)(q31;q24), results in a SLC44A1-PRKCA fusion in papillary glioneuronal tumors and is thought to be responsible for the pathogenesis of the disease (56). IGF2BP3-PRKCA and TANC2-PRKCA fusions were found in lung squamous cell carcinoma and correlate with PRKCA overexpression, suggestive of being the primary oncogenic events. SPNS1-PRKCB, ADCY9-PRKCB and GGA2-PRKCB fusions have been discovered in lung adenocarcinoma, lung squamous cell carcinoma and low-grade glioma. PRKCB fusions remove the N-terminal autoinhibitory domain, effectively activating the kinase.


In some pilocytic astrocytomas, a tandem duplication at 3p25 produces the in-frame, oncogenic fusion SRGAP3-RAF1 and leads to elevated kinase activity (57). Additionally, a presumably reciprocal translocation between ESRP1 and RAF1 in prostate cancer can form a highly expressed gene fusion resulting in the loss of the RAS-binding domain of RAF1. Loss of the RAS-binding domain is indicative of a constitutively active fusion protein that could be targeted by RAF inhibitors (58).


V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA), previously known as NFKB3, encodes a principle protein associated with heterodimer formation and activation of the transcription factor NF-kB. Fusion of RELA to the poorly characterized gene C11orf95 after chromothripis is prevalent in two-thirds of supranatenorial ependymomas (59). Furthermore, mouse cerebral implantation of neural stem cells with red fluorescent protein-tagged versions of wildtype RELA and RELA fusions showed the fusion proteins as oncogenic in nature and resulted in tumor formation with similar characteristics of ependymoma (60)


RET, a transmembrane receptor tyrosine kinase, is essential for development, maturation and maintenance in various tissues. RET-mediated signals are susceptible to deregulation and subsequent development of many different cancers. Rearrangements of RET at chromosome 10q11.2 can cause fusion proteins that have been described in numerous cancers, notably lung adenocarcinoma (61) and thyroid cancer (62, 63). Between 20% and 40% of papillary thyroid carcinomas contain RET translocations, most commonly the RET-CCDC6 and RET-NCOA4 fusions caused by an intrachromosomal inversion on chromosome 10 (64). Chimeric RET fusions to various partner genes also occur in 1-2% of non-small cell lung cancer (NSCLC) (65, 66) and are mutually exclusive of mutations in EGFR, KRAS, ALK, HER2 and BRAF (67). These chimeric rearrangements occur between the transmembrane and kinase domains of RET result in cytosolic localization, constitutive dimerization and subsequent activation of the kinase. The KIF5B-RET fusion in NSCLC results in a 2- to 30-fold increase in RET transcription, suggesting that RET kinase activity is the oncogenic driver in these cases (68).

Because RET shares high homology with functional domains in other tyrosine kinases, pan-small-molecule tyrosine kinase inhibitors (TKIs) can effectively inhibit RET kinase activity. The FDA approved VEGFR2 and EGFR inhibitor vandetanib, and the MET and VEGFR2 inhibitor cabozantinib along with clinical trials of other multi-kinase inhibitors like sorafenib, nintedanib, ponatinib and levatinib offer promising therapeutic potential for RET fusion-associated tumors.


C-Ros Oncogene 1 (ROS1), located at 4q22, encodes a single-pass transmembrane protein receptor tyrosine kinase that is closely related to ALK. A ROS1 rearrangement in glioblastoma was the first discovered in 1987 (69) and was later characterized as FIG-ROS1 fusion (70). Since then, ROS1 fusions have been observed in chloangiocarcinoma, ovarian cancer, gastric adenocarcinoma, mylofibroblastric tumors, colorectal cancer, angiocarcinomas and non-small cell lung cancer (71-74). ROS1 fusions are potent oncogenic drivers, and oncogenic transformation is thought to occur through constitutive kinase activation. But the exact mechanism of ROS1 dysregulation is still unclear.

ROS1 rearrangements are thought to upregulate PTPN6 and PTPN1 and activate the PP3K/AKT/mTOR, JAK/STAT and MAPK/ERK pathways (75). ROS1 fusions are seen in 1-2% of all NSCLC (76) and, despite the similarity in their clinicopathologic features, are mutually exclusive of ALK and EGFR mutation drivers (77). Due to high homology with ALK, ALK-responsive TKIs have been shown to suppress ROS1 activity and downstream signaling. Treatment of RET fusion-positive NSCLC patients with crizotinib leads to antitumor activity similar to that with ALK-positive fusions (78).


Recurrent fusions involving R-spondin family members RSPO2 and RSPO3 occur in 10% of colorectal cancer. A recurrent EIF3E-RSPO2 fusion in colon tumors is thought to produce functional RSPO2 protein promoted by the EIF3E partner. Similarly, PTPRK exons 1 and 7 are known to fuse with exon 2 of the 5’ fusion partner RSPO3. Whole-genome sequencing reads show simple and complex inversions of the chromosome 6q place PTPRK and RSPO3 close to each other. Additionally, RNA-seq showed that RSPO2 and RSPO3 were more expressed in fusion-positive samples than with samples lacking an R-spondin fusion.

Both RSPO2 and RSPO3 fusions appear to be mutually exclusive with APC and CTNNB1 mutations but not with KRAS and BRAF mutations. It is thought that R-spondin fusions promote Wnt signaling during colon tumor development while driving RSPO2 expression. These findings indicate that R-spondin fusions might be a driver event in colorectal cancer development and represent attractive targets for antibody-based therapy (79).


Telomerase activity is apparent in many cancers, and the TERT gene located on the cytogenetic band 5p15.33 is rearranged in clear cell sarcoma of the kidney (80) and dedifferentiated liposarcoma samples (52). In clear cell sarcoma of the kidney, a novel IRX2-TERT fusion occurs after an interstitial deletion in the short arm of chromosome 5. In this case, TERT was largely upregulated by the IRX2 promoter. In liposarcoma, the non-kinase portion of TRIO fuses to the to TERT and leads to a 100-fold increase in TERT mRNA levels. These TERT fusions may represent novel mechanism for telomerase activation in cancers.


Transcription factor E3 (TFE3) belongs to the MiT family of transcription factors and contains a common helix-loop-helix leucine zipper formation, a transactivation domain and a basic region for DNA binding (81). Translocations of Xp11 cause TFE3 fusions with a variety of partners in renal carcinomas (82, 83) and epithelioid hemangioendothelioma (81). A particularly aggressive subset of renal carcinomas more prominent in children is associated with translocations of Xp11.2, resulting in TFE3 fusions including PRCC-TFE3, PSF-TFE3, SFPQ-TFE3, ASPL-TFE3, NONO-TFE3 and CLTC-TFE3 (82).

While the exact biological nature of the Xp11.2 renal cell carcinoma-associated fusions remains uncertain. Each fusion leads to preservation of the helix-loop-helix leucine zipper domain while the fusion partners tend to be overexpressed within tumors, suggesting that the abnormal TFE3 expression is sufficient for tumor progression. Poor clinical outcome associated with these renal cell carcinomas makes early detection and diagnosis particularly important, as multikinase inhibitors and cytokine immunotherapy attribute to longer progression-free survival in cases (84). Further research in determining the pathway to oncogenesis in this type of renal cell carcinoma is necessary to discover adequate therapeutic targets.


Transcription Factor EB (TFEB), like TFE3, is a member of the MiT family of transcription factors that regulate key developmental pathways in several cell types. Translocation t(6;11)(p21.1;q13) and the resultant fusion of Alpha and the first intron of TFEB, characterizes another rare subset of renal cell carcinomas (85). A multitude of molecular pathways described in carcinogenesis are regulated in part by TFEB, and further research is needed to fully understand the role it plays in oncogenesis.


Thyroid adenoma-associated gene (THADA)—appropriately named for THAD fusions in thyroid adenomas—is located at 2p21 and spans approximately 430 kb and 38 exons. Translocations of 2p21 account for approximately 20% of benign thyroid tumors and hyperplasias of follicular epithelial origin (86). Translocations result in a truncation after exon 28, and the various sequences that fuse to it are not related to any gene, indicating that THADA truncation is the critical driver for tumor growth (87).


TMPRSS2 is a prostate-specific gene that encodes a protein belonging to the serine/protease family and contains a transmembrane domain, receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. The fusion of TMPRSS2 to the ETS transcription factor ERG is a predominant molecular subtype of prostate cancer and is attributed to approximately 50% of cases of the disease (30, 88) and in 20% of high-grade prostatic intraepithelial neoplasia lesions (89). While the exact mechanism of tumorigenesis remains unclear, the TMPRSS2-ERG fusion is known to play a roll in prostate cancer cell migration and invasion (90) and is thought to have a more aggressive phenotype (91). The fusion junction of the cancer specific mRNA sequence can be targeted for protein knockdown by siRNA delivered by liposomal nanovectors and is thought to be a promising therapeutic target for this molecular subset of prostate cancers (92).




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