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The Lancet. Oncology Feb 2020Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive...
BACKGROUND
Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.
METHODS
An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).
FINDINGS
Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.
INTERPRETATION
Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.
FUNDING
Ignyta/F Hoffmann-La Roche.
Topics: Aged; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Gene Fusion; Humans; Indazoles; Male; Membrane Glycoproteins; Middle Aged; Neoplasm Metastasis; Neoplasms; Protein Kinase Inhibitors; Receptor, trkA; Receptor, trkB; Receptor, trkC; Receptors, Nerve Growth Factor; Time Factors; Treatment Outcome
PubMed: 31838007
DOI: 10.1016/S1470-2045(19)30691-6 -
Cell Jul 2020Soybean is one of the most important vegetable oil and protein feed crops. To capture the entire genomic diversity, it is needed to construct a complete high-quality...
Soybean is one of the most important vegetable oil and protein feed crops. To capture the entire genomic diversity, it is needed to construct a complete high-quality pan-genome from diverse soybean accessions. In this study, we performed individual de novo genome assemblies for 26 representative soybeans that were selected from 2,898 deeply sequenced accessions. Using these assembled genomes together with three previously reported genomes, we constructed a graph-based genome and performed pan-genome analysis, which identified numerous genetic variations that cannot be detected by direct mapping of short sequence reads onto a single reference genome. The structural variations from the 2,898 accessions that were genotyped based on the graph-based genome and the RNA sequencing (RNA-seq) data from the representative 26 accessions helped to link genetic variations to candidate genes that are responsible for important traits. This pan-genome resource will promote evolutionary and functional genomics studies in soybean.
Topics: Base Sequence; Chromosomes, Plant; Domestication; Ecotype; Gene Duplication; Gene Expression Regulation, Plant; Gene Fusion; Genome, Plant; Geography; Molecular Sequence Annotation; Phylogeny; Polymorphism, Single Nucleotide; Polyploidy; Glycine max
PubMed: 32553274
DOI: 10.1016/j.cell.2020.05.023 -
International Journal of Molecular... Aug 2022Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth... (Review)
Review
Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein-FGFR3-TACC3 fusion-is prevalent in 3-4% of human glioblastoma. The fusion protein leads to the constitutively activated kinase signaling of FGFR3 and thereby promotes cell proliferation and tumor progression. The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice.
Topics: Gene Fusion; Glioblastoma; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Oncogene Fusion; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 35955806
DOI: 10.3390/ijms23158675 -
Annals of Oncology : Official Journal... Nov 2019Due to the efficacy of tropomyosin receptor kinase (TRK) inhibitor therapy and the recent Food and Drug Administration approval of larotrectinib, it is now clinically... (Review)
Review
Due to the efficacy of tropomyosin receptor kinase (TRK) inhibitor therapy and the recent Food and Drug Administration approval of larotrectinib, it is now clinically important to accurately and efficiently identify patients with neurotrophic TRK (NTRK) fusion-driven cancer. These oncogenic fusions occur when the kinase domain of NTRK1, NTRK2 or NTRK3 fuse with any of a number of N-terminal partners. NTRK fusions are characteristic of a few rare types of cancer, such as secretory carcinoma of the breast or salivary gland and infantile fibrosarcoma, but they are also infrequently seen in some common cancers, such as melanoma, glioma and carcinomas of the thyroid, lung and colon. There are multiple methods for identifying NTRK fusions, including pan-TRK immunohistochemistry, fluorescence in situ hybridisation and sequencing methods, and the advantages and drawbacks of each are reviewed here. While testing algorithms will obviously depend on availability of various testing modalities and economic considerations for each individual laboratory, we propose triaging specimens based on histology and other molecular findings to most efficiently identify tumours harbouring these treatable oncogenic fusions.
Topics: Gene Fusion; Humans; Membrane Glycoproteins; Neoplasms; Oncogene Proteins, Fusion; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Receptor, trkB; Receptor, trkC
PubMed: 31738428
DOI: 10.1093/annonc/mdz384 -
Leukemia May 2023Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we...
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Adult; Middle Aged; Aged; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Histone-Lysine N-Methyltransferase; Myeloid-Lymphoid Leukemia Protein; Gene Fusion
PubMed: 37019990
DOI: 10.1038/s41375-023-01877-1 -
Thoracic Cancer Nov 2022Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At...
Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.
Topics: Humans; Receptor, trkC; Receptor, trkA; In Situ Hybridization, Fluorescence; Consensus; Gene Fusion; Neoplasms
PubMed: 36127731
DOI: 10.1111/1759-7714.14644 -
Pediatric Blood & Cancer Apr 2022Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100%... (Review)
Review
Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.
Topics: Adolescent; Child; Gene Fusion; Humans; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Risk Assessment; Risk Factors
PubMed: 35129294
DOI: 10.1002/pbc.29511 -
Diagnostic Pathology Apr 2021Solitary Fibrous Tumor (SFT) is a distinct soft tissue neoplasm associated with NAB2-STAT6 gene fusion. It can involve a number of anatomic sites and exhibits a wide... (Review)
Review
The many faces of solitary fibrous tumor; diversity of histological features, differential diagnosis and role of molecular studies and surrogate markers in avoiding misdiagnosis and predicting the behavior.
BACKGROUND
Solitary Fibrous Tumor (SFT) is a distinct soft tissue neoplasm associated with NAB2-STAT6 gene fusion. It can involve a number of anatomic sites and exhibits a wide spectrum of histological features.
MAIN BODY
Apart from diversity in morphological features seen even in conventional SFT, two histologic variants (fat-forming and giant cell-rich) are also recognized. In addition, a malignant form and dedifferentiation are well recognized. Owing to diverse histological features and involvement of diverse anatomic locations, SFT can mimic other soft tissue neoplasms of different lineages including schwannoma, spindle cell lipoma, dermatofibrosarcoma protuberans, liposarcoma, gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma. SFT is classified as an intermediate (rarely metastasizing) tumor according to World Health Organization Classification of Tumors of Soft tissue and Bone, 5th edition. The management and prognosis of SFT differs from its malignant mimics and correct diagnosis is therefore important. Although SFT expresses a distinct immunohistochemical (IHC) profile, the classic histomorphological and IHC profile is not seen in all cases and diagnosis can be challenging. NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its IHC surrogate marker signal transducer and activator of transcription 6 (STAT6) has also shown significant sensitivity and specificity. However, few recent studies have reported STAT6 expression in other soft tissue neoplasms.
CONCLUSION
This review will focus on describing the diversity of histological features of SFT, differential diagnoses and discussing the features helpful in distinguishing SFT from its histological mimics.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Diagnosis, Differential; Diagnostic Errors; Female; Gene Fusion; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Diagnostic Techniques; Mutation; Predictive Value of Tests; Prognosis; Repressor Proteins; STAT6 Transcription Factor; Solitary Fibrous Tumors; Young Adult
PubMed: 33879215
DOI: 10.1186/s13000-021-01095-2 -
Acta Neuropathologica Nov 2021Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly...
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
Topics: Biomarkers, Tumor; Brain Neoplasms; Child; Child, Preschool; Female; Humans; Kruppel-Like Transcription Factors; Male; Neoplasms, Neuroepithelial; Oncogene Fusion; Oncogene Proteins, Fusion; Repressor Proteins
PubMed: 34417833
DOI: 10.1007/s00401-021-02354-8 -
Nature Communications Apr 2023Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by...
Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.
Topics: Alternative Splicing; Amyotrophic Lateral Sclerosis; Cadaver; Cohort Studies; Datasets as Topic; DNA Damage; DNA-Binding Proteins; Gene Fusion; Genomic Instability; Induced Pluripotent Stem Cells; Motor Neurons; Mutation; Spinal Cord; Transcriptome; Humans
PubMed: 37080969
DOI: 10.1038/s41467-023-37630-6