scholarly journals OR28-04 Identification of Novel and Rare Receptor Tyrosine Kinase Fusions in Thyroid Fine Needle Aspirates

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lori J Wirth ◽  
Elizabeth G Grubbs ◽  
Masha J Livhits ◽  
Steven I Sherman ◽  
Steven P Weitzman ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Chromosomal Rearrangements ◽  
Kinase Domain ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Rna Seq ◽  
Fine Needle Aspirates ◽  
Genomic Markers ◽  
Treatment Naïve

Abstract Introduction: Receptor tyrosine kinases (RTKs) initiate signaling cascades, including growth and differentiation. Activation can occur through chromosomal rearrangements that lead to gene fusions. RTK fusions are potential targets for small molecule inhibitors to treat advanced cancers. The original Afirma Xpression Atlas (XA) reported 761 selected variants and 130 fusion pairs in Bethesda III/IV Afirma Genomic Sequencing Classifier (GSC) suspicious or Bethesda V/VI nodules. The landscape of additional potentially actionable gene fusions has not been explored in treatment-naïve patients. Methods: Anonymized RNA-seq data from >37,000 Bethesda III-VI samples were examined with STAR-fusion to determine gene/gene fusions. All samples were examined for NTRK1, NTRK3, RET, ALK, and BRAF fusions, regardless of fusion partner. Fusions were evaluated for being in-frame, with an intact kinase domain at the 3’ end of the fusion pair. Fusion pairs not currently reported by XA and not reported in thyroid TCGA fusion data are denoted “additional”. All fusion pairs were searched for in the literature and public fusion databases. Results: Examining the Veracyte clinical database revealed 7 additional NTRK1/3 fusions, with 3 NTRK fusions observed more than once - SQSTM1/NTRK3, VIM/NTRK3, and EML4/NTRK3. One of the 7 NTRK fusions had not been previously reported. Eight additional ALK fusions were identified, with 4 observed more than once- ITSN2/ALK, PPP1R21/ALK, PDE8B/ALK, NPAT/ALK. Five of these 8 ALK fusions had not been previously described. Seventeen additional RET fusions were identified, with 5 observed recurrently - KIAA1217/RET, AFAP1L2/RET, ACBD5/RET, SQSTM1/RET, and TFG/RET. Six of the 17 RET fusions had not been previously reported. Seventy-two additional BRAF fusions were identified, and 58 of them have not been previously reported. Eight of the 72 BRAF fusions were observed more than once. Examining >50,000 Afirma samples, NTRK1, NTRK3, RET, ALK, or BRAF fusions were not identified among the Afirma GSC Benign, and were present in 3.2% of 16,594 Bethesda III/IV Afirma GSC Suspicious samples, and 8.0% of 1,692 Bethesda V/VI samples. Correlation with surgical histology is unknown. Conclusions: By examining a large cohort of patients with an unbiased, whole-transcriptome RNA-seq assay, we identified potentially actionable kinase fusions in thyroid nodules beyond those described in TCGA. All fusions described here are either novel and not previously reported, rarely reported in one or two case studies, or not described in thyroid cancers. Additional NTRK, ALK, RET and BRAF fusions were found, all of which may be targeted with specific kinase inhibitors currently available. Future studies may determine genotype-phenotype correlations regarding the natural history of these neoplasms. Because of the potential clinical implications of these genomic markers for patient management, all 104 fusions described here are now included among the 235 gene pairs reported by the expanded Afirma XA.

New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2429-2437 ◽  
Author(s):  
Federica Toffalini ◽  
Jean-Baptiste Demoulin
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Chromosomal Rearrangements ◽  
Point Mutations ◽  
Large Cell ◽  
Kinase Domain ◽  
Leukemic Cells

Abstract A large number of alterations in genes encoding receptor tyrosine kinase (RTK), namely FLT3, c-KIT, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, and the anaplastic large cell lymphoma kinase (ALK), have been found in hematopoietic malignancies. They have drawn much attention after the development of tyrosine kinase inhibitors. RTK gene alterations include point mutations and gene fusions that result from chromosomal rearrangements. In both cases, they activate the kinase domain in the absence of ligand, producing a permanent signal for cell proliferation. Recently, this simple model has been refined. First, by contrast to wild-type RTK, many mutated RTK do not seem to signal from the plasma membrane, but from various locations inside the cell. Second, their signal transduction properties are altered: the pathways that are crucial for cell transformation, such as signal transducer and activator of transcription (STAT) factors, do not necessarily contribute to the physiologic functions of these receptors. Finally, different mechanisms prevent the termination of the signal, which normally occurs through receptor ubiquitination and degradation. Several mutations inactivating CBL, a key RTK E3 ubiquitin ligase, have been recently described. In this review, we discuss the possible links among RTK trafficking, signaling, and degradation in leukemic cells.

ALK and ROS1 gene rearrangements detected in colorectal cancer (CRC) by fluorescence in situ hybridization (FISH).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3545-3545 ◽  
Author(s):  
Andrew James Weickhardt ◽  
Teresa T. Nguyen ◽  
Diego D. Paskulin ◽  
Anh T. Le ◽  
Dara Aisner ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Screening Tests ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Alk Rearrangement ◽  
Highly Sensitive ◽  
Lung Adenocarcinomas ◽  
Probe Set

3545 Background: Activation of ROS1 and ALK tyrosine kinases through gene fusions lead to unchecked cell proliferation and transformation. ROS1 and ALK gene fusions were found in about 5% and 2% of lung adenocarcinomas and are highly sensitive to specific tyrosine kinase inhibitors. This study aimed at identifying the presence of ROS1 and ALKrearrangements in CRC using FISH technology. Methods: Arrayed specimens of metastatic CRC (mCRC) patients were tested with a 4-target, 4-color break-apart FISH probe set (Abbott Molecular) designed to simultaneously evaluate the genomic status of ROS1 and ALK. Fused 3’/5’ signals of each gene were considered negative for rearrangement; single 3’/single 5’ (for ROS1) and split 3’-5’ or single 3’ (for ALK) were considered positive for rearrangement. Results: Among 236 mCRC patients tested, two were positive for ROS1 (single 3’ROS1 signals in 39% and 61% of tumor cells) and one was positive for ALK rearrangement (single 3’ALK in 41% of tumor cells). The upper cut-off for positive FISH patterns in the negative specimens was identified as <15% both for ROS1 and ALK. Interestingly, the ALK+ patient displayed intra-tumoral heterogeneity, detected in the tissue cores and confirmed in two resection blocks. The fusion partner for ALK was identified as EML4 by PCR-based tests and sequencing. The fusion partner(s) for ROS1 remains to be identified by other technologies. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. Conclusions: The novel FISH probe set was effective to identify the first cases of ROS1 rearrangements in CRC and re-confirm the occurrence of ALK rearrangements. This supports further evaluation of mCRC cases for ROS1 and ALK gene fusions as these may represent new targets for evaluation in clinical trials. Tumor heterogeneity in the ALK rearrangement must be addressed for screening tests. (Partially supported by research grant from Abbott Molecular and the Colorado CCSG P30CA046934).

scholarly journals Generation of An Endogenous FGFR2–BICC1 Gene Fusion/58 Megabase Inversion Using Single-Plasmid CRISPR/Cas9 Editing in Biliary Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2460
Author(s):  
Andreas Reicher ◽  
Antoneicka L Harris ◽  
Felix Prinz ◽  
Tobias Kiesslich ◽  
Miaoyan Wei ◽  
...  
Keyword(s):  
Cell Lines ◽  
Rna Binding ◽  
Human Cancer ◽  
Chromosomal Rearrangements ◽  
Growth Factor Receptor ◽  
Fusion Product ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Endogenous Gene ◽  
Fgfr2 Gene

Fibroblast growth factor receptor 2 (FGFR2) gene fusions are bona fide oncogenic drivers in 10–15% of intrahepatic cholangiocarcinoma (CCA), yet currently there are no cell lines publically available to study endogenous FGFR2 gene fusions. The ability of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to generate large yet precise chromosomal rearrangements has presented the possibility of engineering endogenous gene fusions for downstream studies. In this technical report, we describe the generation of an endogenous FGFR2–Bicaudal family RNA binding protein 1 (BICC1) fusion in multiple independent cholangiocarcinoma and immortalized liver cell lines using CRISPR. BICC1 is the most common FGFR2 fusion partner in CCA, and the fusion arises as a consequence of a 58-megabase-sized inversion on chromosome 10. We replicated this inversion to generate a fusion product that is identical to that seen in many human CCA. Our results demonstrate the feasibility of generating large megabase-scale inversions that faithfully reproduce human cancer aberrations.

ARG tyrosine kinase activity is inhibited by STI571

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2440-2448 ◽  
Author(s):  
Keiko Okuda ◽  
Ellen Weisberg ◽  
D. Gary Gilliland ◽  
James D. Griffin
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Fusion Partner ◽  
Induced Apoptosis

Abstract The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)β receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFβR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFβR, and TEL/ARG with an IC50 of approximately 0.5 μM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.

scholarly journals Fusion detection and quantification by pseudoalignment

2017 ◽  
Author(s):  
Páll Melsted ◽  
Shannon Hateley ◽  
Isaac Charles Joseph ◽  
Harold Pimentel ◽  
Nicolas Bray ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Clinical Use ◽  
Gene Fusions ◽  
Fusion Genes ◽  
Rna Seq ◽  
Sequencing Data ◽  
Transcript Quantification ◽  
Novel Approach ◽  
Fusion Detection

RNA sequencing in cancer cells is a powerful technique to detect chromosomal rearrangements, allowing for de novo discovery of actively expressed fusion genes. Here we focus on the problem of detecting gene fusions from raw sequencing data, assembling the reads to define fusion transcripts and their associated breakpoints, and quantifying their abundances. Building on the pseudoalignment idea that simplifies and accelerates transcript quantification, we introduce a novel approach to fusion detection based on inspecting paired reads that cannot be pseudoaligned due to conflicting matches. The method and software, called pizzly, filters false positives, assembles new transcripts from the fusion reads, and reports candidate fusions. With pizzly, fusion detection from raw RNA-Seq reads can be performed in a matter of minutes, making the program suitable for the analysis of large cancer gene expression databases and for clinical use. pizzly is available at https://github.com/pmelsted/pizzly

scholarly journals Phase-separation of EML4-ALK variant 3 is dependent upon an active ALK conformation

2020 ◽  
Author(s):  
Josephina Sampson ◽  
Mark W. Richards ◽  
Jene Choi ◽  
Andrew M. Fry ◽  
Richard Bayliss
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Liquid Droplet ◽  
Salt Bridge ◽  
Droplet Formation ◽  
Kinase Domain ◽  
Liquid Droplets ◽  
Cellular Localisation ◽  
Inactivating Mutation

ABSTRACTOncogenic fusions involving tyrosine kinases are common drivers of non-small cell lung cancer (NSCLC). There are at least 15 different variants of the EML4-ALK fusion, all of which have a similar portion of ALK that includes the kinase domain, but different portions of EML4. Targeted treatment with ALK tyrosine kinase inhibitors (TKIs) has proven effective but patient outcomes are variable. Here, we focus on one common variant, EML4-ALK V3, which drives an aggressive form of the disease. EML4-ALK V3 protein forms cytoplasmic liquid droplets that contain the signalling proteins GRB2 and SOS1. The TKIs ceritinib and lorlatinib dissolve these droplets and the EML4-ALK V3 protein re-localises to microtubules, an effect recapitulated by an inactivating mutation in the ALK catalytic site. Mutations that promote a constitutively active ALK stabilise the liquid droplets even in the presence of TKIs, indicating that droplets do not depend on kinase activity per se. Uniquely, the TKI alectinib promotes droplet formation of both the wild-type and catalytically inactive EML4-ALK V3 mutant, but not in a mutant that disrupts a hallmark of the kinase activity, the Lys-Glu salt-bridge. We propose that EML4-ALK V3 liquid droplet formation occurs through transient dimerization of the ALK kinase domain in its active conformation in the context of stable EML4-ALK trimers. Our results provide insights into the relationship between ALK activity, conformational state and the sub-cellular localisation of EML4-ALK V3 protein, and reveal the different effects of structurally divergent ALK TKIs on these properties.

scholarly journals Fusion Genes and RNAs in Cancer Development

2021 ◽  
Vol 7 (1) ◽  
pp. 10
Author(s):  
Kenzui Taniue ◽  
Nobuyoshi Akimitsu
Keyword(s):  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Chromosomal Rearrangements ◽  
Tumor Development ◽  
Cancer Development ◽  
Gene Fusions ◽  
Fusion Genes ◽  
Therapeutic Implications ◽  
Downstream Signaling

Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis.

Glycosylation and Surface Localization Are Required for FLT3 Activation but Not for FLT3/ITD.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2748-2748
Author(s):  
Allen Williams ◽  
Sina Koch ◽  
Thiede Christian ◽  
Patrick Brown ◽  
Mark Levis ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Intracellular Localization ◽  
Point Mutations ◽  
Surface Expression ◽  
Kinase Domain ◽  
Class Iii ◽  
Core Oligosaccharide

Abstract Abstract 2748 Poster Board II-724 FLT3 is a class III receptor tyrosine kinase that is normally activated on the surface of hematopoietic cells by binding of FLT3 ligand (FL). After FL binding, phosphorylation leads to activation of multiple signaling pathways and to down-regulation of surface expression due to internalization of the receptor. Activating mutations of FLT3 are commonly observed in acute myeloid leukemia (AML) and are associated with a poor prognosis. About 33% of AML cases contain constitutively activated FLT3 either as point mutations in the kinase domain or as internal tandem duplications (ITDs) in or near the juxtamembrane domain. These mutant forms of FLT3 do not require FL and localize both to an intracellular compartment as well as to the plasma membrane. We identified two subclones of TF-1/ITD cells that expressed almost exclusively the intracellular form of FLT3/ITD. These cells were resistant to inhibition by tyrosine kinase inhibitors (TKIs) in the absence of any resistance conferring mutation within FLT3 itself. MTT assays revealed that the IC50 values increased by ∼10-fold for PKC412 in clones TF-1/ITD P8 (P8) and TF-1/ITD P65 (P65) compared to parental TF-1/ITD cells. A high level of pan-resistance was noted for lestaurtinib, sunitinib, sorafenib and AGL2043. In agreement with the MTT data, Western blotting shows that FLT3/ITD in both P8 and P65 was not inhibited by any of the tested TKIs. Blots show that inhibition of FLT3/ITD in TF-1/ITD cells led to formation of more of the fully glycosylated mature receptor. Immunofluorescence microcsopy shows that FLT3/ITD inhibition was accompanied by translocation to the plasma membrane. Unlike the FLT3 TKIs, the src inhibitor PP2 inhibited FLT3 phosphorylation in the P8 and P65 clones. However, FLT3/ITD inhibition by PP2 in P8 and P65 did not promote receptor maturation. Immunofluorescence microscopy shows that wild-type FLT3 resides primarily in the plasma membrane and FLT3/ITD in TF-1/ITD cells that has been inhibited translocates from the trans-Golgi network to the plasma membrane. FLT3/ITD in clones P8 and P65 appear to be restricted to the endoplasmic reticulum, and inhibition by PP2 did not cause translocation to the surface. We wanted to test whether FLT3 with modified glycosylation could mimic the phenotype seen in the P8 and P65 clones. Cells treated with the deglycosylation agents, tunicamycin or swainsonine, produced altered glycosylation patterns of FLT3 and FLT3/ITD. FLT3 could not be stimulated by FL following treatment with tunicamycin, but it could still be stimulated by FL after partial deglycosylation by treatment with swainsonine. These results indicate that FLT3 need not be in its mature form to be fully activated by FL, but earlier steps during glycosylation are required for activation. On the other hand, FLT3/ITD appears to be activated soon after translation and prior to glycosylation as evidenced by its phosphorylation in the absence of even the 14-sugar core oligosaccharide whose transfer was prevented by tunicamycin. It has been reported that localization of receptor tyrosine kinases may affect downstream signaling, but we did not observe noticeable changes in Stat5 or MAP Kinase activation in FLT3/ITD cells treated with tunicamycin or swainsonine. (In one published study, a FLT3/ITD that was altered to anchor to the E.R. showed an increase in Stat3 activation but a decrease in Stat5, Erk and Akt activation.) Thus, it is likely that there are some components of receptor trafficking and/or localization that contribute to transformation phenotypes. Aberrant intracellular localization has been previously documented for the PDGF and Kit receptors in a human glioblastoma and gastrointestinal stromal tumor, respectively. This suggests that altered localization may also contribute to FLT3 transformation phenotype and may affect inhibitor resistance as well. Disclosures: Christian: Novartis: Research Funding.

NTRK1 gene fusions as a novel oncogene target in lung cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8023-8023 ◽  
Author(s):  
Robert Charles Doebele ◽  
Aria Vaishnavi ◽  
Marzia Capelletti ◽  
Anh T. Le ◽  
Severine Kako ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Kinase Domain ◽  
Cloning And Expression ◽  
Egfr Mutations ◽  
Fish Analysis ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Investigation Methods ◽  
Trk Inhibitors

8023 Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.

Incidence of ERBB gene fusions (EGFR, ERBB2, ERBB4) across tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3091-3091
Author(s):  
Laura Schubert ◽  
Andrew Elliott ◽  
Robert Charles Doebele ◽  
Emil Lou ◽  
Hossein Borghaei ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Gastroesophageal Junction ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Data Sets ◽  
Gene Fusions ◽  
Cancer Subtypes ◽  
Multiple Tumor ◽  
Public Data ◽  
Tumor Types

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing > 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( > 60% average across public data sets), with higher co-mutation rates ( > 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.

Sign in / Sign up

Export Citation Format

Share Document