Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF
Jaclyn F. HechtmanAhmet ZehirRona YaegerLu WangSumit MiddhaTao ZhengDavid M. HymanDavid B. SolitMaria E. ArcilaLaetitia BorsuJinru ShiaEfsevia VakianiLeonard B. SaltzMarc Ladanyi
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Abstract:
Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and MAP2K1 (MEK1) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, and ETV6-NTRK3. Only 1 of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.Targetable kinase alterations were identified in a subset of advanced colorectal carcinoma patients, preferentially associated with wild-type RAS/RAF, and may predict poor response to standard anti-EGFR therapy.Keywords:
Targeted Therapy
ETV6
Rearrangements of 12p, resulting from deletions or translocations, are common findings in hematologic malignancies. In many cases, these rearrangements target the ETV6 gene (previously called TEL) located at 12p13. Various partner genes have been implicated in the formation of fusion genes with ETV6. These include PDGFRB, JAK2, NTRK3, ABL2, and ABL1, each of which encodes for proteins with tyrosine kinase activity. To date, ETV6/ABL1 transcripts have been detected in only four patients with a leukemic disorder. Here, we describe one adult with chronic myeloid leukemia and a child with T-cell acute lymphocytic leukemia with ETV6/ABL1. Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement. Molecular analysis showed the presence of two fusion transcripts in both patients as the result of alternative splicing, questioning the suggested role of these transcripts in the lineage specificity. Clinical findings of these patients were compared to those of previously reported cases, and the possible clinical and biological similarities between ETV6/ABL1 and other fusion genes leading to increased tyrosine kinase activity are discussed.
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PDGFRB
ABL
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Chimeric gene
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ETV6
ABL
Chimeric gene
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Secretory carcinoma (SC) is a low-grade salivary gland carcinoma similar to secretory breast carcinoma harboring the ETV6-NTRK3 fusion gene, that was first proposed as a distinct disease entity in 2010 by Skálová et al. SC has heterogeneous histopathological manifestations, so that definitive diagnosis of the tumor by histopathological examination is difficult. Many fusion partners of ETV6 are known in other malignant tumors. In the case of SC also, previously unknown fusion partners of ETV6 (ETV6-X) have been reported recently. Herein, we report a case of SC of the submandibular gland harboring an ETV6-X fusion gene. A 32-year-old man presented to our department with a mass in his right submandibular region that he had first noticed one month earlier. We diagnosed the mass as a submandibular gland tumor and performed submandibular gland excision. The postoperative histopathological findings led to suspicion of the tumor as a SC. Subsequently, FISH analysis led to a confirmed the diagnosis of SC with an ETV6-X fusion gene. No evidence of recurrence was noted during postoperative follow-up of the patient for 20 months without any further therapy. Because of the difficulty in the histological diagnosis and absence of any availability of established treatments for tumors harboring the NTRK family genes, it is important to perform genetic examination for confirmatory diagnosis in patients with suspected SC.
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ETV6::ABL1 gene fusion is a rare recurrent genomic rearrangement associated with hematologic malignancies, and frequently occurs with additional anomalies. Due to the opposite chromosome orientations of the ETV6 and ABL1 genes, an oncogenic in-frame ETV6::ABL1 gene fusion cannot be formed by a simple translocation. The molecular mechanism of the ETV6::ABL1 fusion and the significance of co-occurring anomalies are not fully understood. We characterized genomic alterations in an individual with ETV6::ABL1 gene-fusion-positive myeloid neoplasm using various genomic technologies. Our findings uncovered a molecular mechanism of the ETV6::ABL1 fusion, in which a paracentric inversion within the short arm of chromosome 12 (12p) and a translocation between the long arm of a chromosome 9 and the 12p with the inversion were involved. In addition, we detected multiple additional anomalies in the individual, and our findings suggested that the ETV6::ABL1 fusion occurred as a secondary event in a subset of cells with the additional anomalies. We speculate that the additional anomalies may predispose to further pathogenic changes, including ETV6::ABL1 fusion, leading to neoplastic transformation.
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Genetic analysis of high-grade glial tumors in children has revealed the presence of the ETV6-NTRK3 gene fusion in a small number of highly aggressive‐appearing neoplasms. Identification of this gene fusion is important in that these patients may benefit from new, targeted therapies. Clinical presentation, imaging, and pathologic confirmation were obtained from 5 patients with confirmed ETV6-NTRK3 gene fusion. This case series may raise awareness of this entity and prompt genetic evaluation.
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Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET , ETV6-MAML3 , and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6 , RET , and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients’ age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET -targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B . The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non- ETV6 5′ fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
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A fusion gene that results from a chromosomal translocation t(9;12)(p24;p13) which fuses the 5' half of the ETV6 gene to the 3' portion of the JAK2 gene. This fusion is associated with acute myeloid and lymphoid leukemias.
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The MN1::ETV6 gene fusion resulting from t(12;22)(p13;q12) has been rarely reported in myeloid neoplasms. We describe a 69-year-old male with newly diagnosed acute myeloid leukemia (AML) with erythroid differentiation and t(12;22)(p13;q12) demonstrated by conventional chromosome studies. Subsequent fluorescence in situ hybridization studies demonstrated a balanced ETV6 gene rearrangement (at 12p13). To further characterize this translocation, whole-genome sequencing was performed which confirmed t(12;22) with breakpoints involving the MN1 and ETV6 genes. Herein, we describe our case and review the literature to summarize the clinical and laboratory findings in patients with this rare but recurrent MN1::ETV6 gene fusion observed in myeloid neoplasms. Importantly, this case expands the clinical spectrum associated with the MN1::ETV6 gene fusion to include AML with erythroid differentiation. Lastly, this case demonstrates the importance of moving toward more comprehensive molecular testing to fully characterize the driver events in neoplastic genomes.
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Objective:To investigate the expression of the fusion gene of ETV6-NTRK3 and its feature in hematological malignagcy;explore the relationship between the fusion gene and its immunophenotype;evaluate its value in the clinical dignosis,therapy and prognosis.Method:Collect 47 samples which were untreated and 14 samples of AML-M2 which were therapied by two courses with standard chemotherapy regimen,to amplify specific fusion gene fragment by RT-PCR method,flow cytometry was applied to analyze the immunophenotype of the 47 samples.Result:Under the ultraviolet light,two samples expressed ETV6-NTRK3 fusion gene among 47 samples.The positive rate was 14% in AML-M2(2/14).We could not detect any reciprocal products of NTRK3-ETV6.A nomal NTRK3 message was also undetectable.Conclusion:①About 14% AML-M2 can express ETV6-NTRK3 fusion gene t(12;15)(p13;q25).All of them are AML-M2a.②The present standard therapic program can not take any effect on the patients with ETV6-NTRK3 fusion gene;which is refractory leukemia,so the prognosis is badly.③According to the FCM immunophenotype analysis,the patients with ETV6-NTRK3 fusion gene expressed CD13 and CD33,and the expression of CD13 is stronger than that of CD33.No-CD14 expression.It signified the leukemic cell of the patients originated early,differentiated badly,and was high-grade malignancy.
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