المؤلفون: Nakata, Eiji^1,2 (AUTHOR) eijinakata8522@yahoo.co.jp, Osone, Tatsunori³ (AUTHOR), Ogawa, Toru⁴ (AUTHOR), Taguchi, Tomoyuki⁴ (AUTHOR), Hattori, Kana⁴ (AUTHOR), Kohsaka, Shinji⁵ (AUTHOR)

المصدر: Cancer Medicine. Jun2024, Vol. 13 Issue 12, p1-12. 12p.

مصطلحات موضوعية: *GENE fusion, *GENE rearrangement, *THYROID cancer, *TROPOMYOSINS, *GENE families, *HEAD & neck cancer

مصطلحات جغرافية: JAPAN

مستخلص: Background: Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases. Intra‐ or inter‐chromosomal gene rearrangements produce NTRK gene fusions encoding fusion proteins which are oncogenic drivers in various solid tumors. Methods: This study investigated the prevalence of NTRK fusion genes and identified fusion partners in Japanese patients with solid tumors recorded in the Center for Cancer Genomics and Advanced Therapeutics database of comprehensive genomic profiling test. Results: In the analysis population (n = 46,621), NTRK fusion genes were detected in 91 patients (0.20%). The rate was higher in pediatric cases (<18 years; 1.69%) than in adults (0.16%). NTRK gene fusions were identified in 21 different solid tumor types involving 38 different partner genes including 22 (57.9%) previously unreported NTRK gene fusions. The highest frequency of NTRK gene fusions was head and neck cancer (1.31%) and thyroid cancer (1.31%), followed by soft tissue sarcoma (STS; 0.91%). A total of 97 NTRK fusion gene partners were analyzed involving mainly NTRK1 (49.5%) or NTRK3 (44.2%) gene fusions. The only fusion gene detected in head and neck cancer was ETV6::NTRK3 (n = 22); in STS, ETV6::NTRK3 (n = 7) and LMNA::NTRK1 (n = 5) were common. Statistically significant mutual exclusivity of NTRK fusions with alterations was confirmed in TP53, KRAS, and APC. NTRK gene fusion was detected from 11 STS cases: seven unclassified sarcoma, three sarcoma NOS, and one Ewing sarcoma. Conclusions: NTRK gene fusion identification in solid tumors enables accurate diagnosis and potential TRK inhibitor therapy. [ABSTRACT FROM AUTHOR]

المؤلفون: Siddika, Most Ayesha¹ (AUTHOR), Ahmed, Khandaker Asif² (AUTHOR), Alam, Mohammad Shamimul¹ (AUTHOR) shamimul@du.ac.bd, Bushra, Jannatul¹ (AUTHOR), Begum, Rowshan Ara¹ (AUTHOR)

المصدر: Scientific Reports. 6/15/2024, Vol. 14 Issue 1, p1-16. 16p.

مصطلحات موضوعية: *MITOCHONDRIAL DNA, *GENE rearrangement, *SCIAENIDAE, *GENETIC variation, *GENETIC distance, *FISH diversity, *COMPARATIVE genomics, *AMBIGUITY

مصطلحات جغرافية: BANGLADESH

مستخلص: The Pama Croaker, Otolithoides pama, is an economically important fish species in Bangladesh. Intra-family similarities in morphology and typical barcode sequences of cox1 create ambiguities in its identification. Therefore, morphology and the complete mitochondrial genome of O. pama, and comparative mitogenomics within the family Sciaenidae have been studied. Extracted genomic DNA was subjected to Illumina-based short read sequencing for De-Novo mitogenome assembly. The complete mitogenome of O. pama (Accession: OQ784575.1) was 16,513 bp, with strong AC biasness and strand asymmetry. Relative synonymous codon usage (RSCU) among 13 protein-coding genes (PCGs) of O. pama was also analyzed. The studied mitogenomes including O. pama exhibited consistent sizes and gene orders, except for the genus Johnius which possessed notably longer mitogenomes with unique gene rearrangements. Different genetic distance metrics across 30 species of Sciaenidae family demonstrated 12S rRNA and the control region (CR) as the most conserved and variable regions, respectively, while most of the PCGs undergone a purifying selection. Different phylogenetic trees were congruent with one another, where O. pama was distinctly placed. This study would contribute to distinguishing closely related fish species of Sciaenidae family and can be instrumental in conserving the genetic diversity of O. pama. [ABSTRACT FROM AUTHOR]

المؤلفون: Zilla, Megan L.¹ (AUTHOR), Naous, Rana¹ (AUTHOR), John, Ivy¹ (AUTHOR) johni@upmc.edu

المصدر: International Journal of Surgical Pathology. Jun2024, Vol. 32 Issue 4, p726-730. 5p.

مصطلحات موضوعية: *GENE rearrangement, *FASCIITIS, *FOS oncogenes, *FLUORESCENCE in situ hybridization, *MYOSITIS, *GENE fusion, *DERMATOMYOSITIS

مستخلص: Ischemic fasciitis is a pseudosarcomatous fibroblastic/myofibroblastic proliferation that shares several overlapping morphological features with proliferative fasciitis and proliferative myositis. Prompted by a recent study that demonstrated FOS gene rearrangements in proliferative fasciitis and proliferative myositis, suggesting that these lesions likely represent examples of "transient neoplasia," we examined a cohort of ischemic fasciitis for similar events. Nine cases of ischemic fasciitis were retrieved from our institutional archives for diagnosis verification, immunostaining for FOSB, and fluorescence in situ hybridization using validated FOS and FOSB break-apart probes. Additionally, RNAseq was performed on a subset of cases. In our cohort, eight out of nine cases of ischemic fasciitis were positive for FOSB IHC, but FISH studies were consistently negative for FOSB and FOS gene rearrangements in all cases. Additionally, RNA sequencing did not detect any gene fusions. These findings suggest that the pathogenesis of ischemic fasciitis is distinct from that of proliferative fasciitis and proliferative myositis. [ABSTRACT FROM AUTHOR]

المؤلفون: Xu, Wei¹ (AUTHOR) xuwei2001@njfu.edu.cn, Tai, Jingzhe¹ (AUTHOR) xiaotai@njfu.edu.cn, He, Ke² (AUTHOR) heke@zafu.edu.cn, Xu, Tangjun¹ (AUTHOR) xutangjun@njfu.edu.cn, Zhang, Gaoji¹ (AUTHOR) zhanggaoji@njfu.edu.cn, Xu, Boyu¹ (AUTHOR) xuboyu@njfu.edu.cn, Liu, Hongyi¹ (AUTHOR) hongyi_liu@njfu.edu.cn

المصدر: Animals (2076-2615). Jun2024, Vol. 14 Issue 11, p1598. 16p.

مصطلحات موضوعية: *BIOLOGICAL classification, *GENE rearrangement, *AQUARIUM fishes, *SEAFOOD markets, *MITOCHONDRIA, *GENOMES, *GENETIC code, *TRANSFER RNA

مستخلص: Simple Summary: To complement the genetic information of the pencilfish, a popular aquarium ornamental fish, we sequenced the mitochondrial genomes of four common pencilfish species. Their genome structure, nucleotide composition, codon usage, and phylogeny were comparatively analyzed. The results indicate that the four mitogenomes exhibited a typical circular structure. The gene order of the four Nannostomus pencilfish was similar to that of other fish. Our phylogenetic analyses support the current classification of the family Lebiasinidae. This study provides new data for the breeding and study of pencilfish. Although the pencilfish is a globally popular economic fish in the aquarium market, its taxonomic classification could be further refined. In order to understand the taxonomy of species of the genus Nannostomus (Characiformes, Lebiasinidae) and their phylogenetic position within the order Characiformes, in this study, we characterized mitochondrial genomes (mitogenomes) from four Nannostomus species for the first time. The four mitogenomes exhibited the typical circular structure, with overall sizes varying from 16,661 bp to 16,690 bp. They contained 13 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and 1 control region (CR). Nucleotide composition analysis suggested that the mitochondrial sequences were biased toward A and T. Bayesian inference and maximum likelihood analyses based on PCGs support the family Lebiasinidae classification, described using four Nannostomus species, clustering together with Lebiasina multimaculata from the same family. The results of this study support the current taxonomic classification of the family Lebiasinidae. Phylogenetic analysis also suggested that gene rearrangement would not significantly impact the phylogenetic relationships within the order Characiformes. These results might provide new data regarding the phylogeny and classification of the order Characiformes, thus providing a theoretical basis for the economic development of aquarium fish markets. [ABSTRACT FROM AUTHOR]

المؤلفون: Yin P. Hung^1,2 yphung@mgh.harvard.edu, Chirieac, Lucian R.^2,3

المصدر: Archives of Pathology & Laboratory Medicine. May2024, Vol. 148 Issue 5, pe77-e89. 13p.

مصطلحات موضوعية: *PREDICTIVE tests, *GENE rearrangement, *CYSTS (Pathology), *IMMUNOHISTOCHEMISTRY, *TUMOR suppressor genes, *ENVIRONMENTAL exposure, *MESOTHELIOMA, *ADENOMATOID tumors, *GENETIC mutation, *MOLECULAR diagnosis, *GENETICS, *BIOMARKERS, *ASBESTOS, *SYMPTOMS

مستخلص: * Context.--Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion. Objective.--To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions. Data Sources.--We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions. Conclusions.--Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered. [ABSTRACT FROM AUTHOR]

المؤلفون: Castañeda-Osorio, Rubén^1,2 (AUTHOR), Belokobylskij, Sergey A.³ (AUTHOR), Jasso-Martínez, Jovana M.^1,4 (AUTHOR), Samacá-Sáenz, Ernesto⁵ (AUTHOR), Kula, Robert R.⁶ (AUTHOR), Zaldívar-Riverón, Alejandro¹ (AUTHOR) azaldivar@ib.unam.mx

المصدر: Invertebrate Systematics. 2024, Vol. 38 Issue 5, p1-14. 14p.

مصطلحات موضوعية: *HYMENOPTERA, *GENE rearrangement, *TRANSFER RNA, *MITOCHONDRIAL DNA, *BRACONIDAE, *MITOCHONDRIA, *MITOCHONDRIAL RNA

مستخلص: Mitochondrial DNA gene organisation is an important source of phylogenetic information for various metazoan taxa at different evolutionary timescales, though this has not been broadly tested for all insect groups nor within a phylogenetic context. The cosmopolitan subfamily Doryctinae is a highly diverse group of braconid wasps mainly represented by ectoparasitoids of xylophagous beetle larvae. Previous molecular studies based on Sanger and genome-wide (ultraconserved elements, UCE; and mitochondrial genomes) sequence data have recovered a non-monophyletic Doryctinae, though the relationships involved have always been weakly supported. We characterised doryctine mitogenomes and conducted separate phylogenetic analyses based on mitogenome and UCE sequence data of ~100 representative doryctine genera to assess the monophyly and higher-level classification of the subfamily. We identified rearrangements of mitochondrial transfer RNAs (tRNAs) that support a non-monophyletic Doryctinae consisting of two separate non-related clades with strong geographic structure ('New World' and 'Old World' clades). This geographic structure was also consistently supported by the phylogenetic analyses preformed with mitogenome and UCE sequence data. These results highlight the utility of the mitogenome gene rearrangements as a potential source of phylogenetic information at different evolutionary timescales. Subfamily Doryctinae constitutes mainly parasitoid and some phytophagous braconid wasps. Molecular studies recovered a non-monophyletic Doryctinae. We characterised several mitogenomes and conducted phylogenetic analyses to assess the monophyly and higher-level classification. We identified rearrangements of mitochondrial transfer RNAs that support a non-monophyletic Doryctinae constituting two separate unrelated clades, also supported by phylogenetic analyses of mitogenome and nuclear data. Utility of the mitogenome rearrangements was highlighted as a potential source of phylogenetic information at different evolutionary timescales. (Image credit: Rubén Castañeda-Osorio.) [ABSTRACT FROM AUTHOR]

المؤلفون: Shi, Zhi-Feng^1,2 (AUTHOR) shizhifeng@fudan.edu.cn, Li, Kay Ka-Wai³ (AUTHOR) kayli@cuhk.edu.hk, Liu, Anthony Pak-Yin^4,5 (AUTHOR), Chung, Nellie Yuk-Fei³ (AUTHOR) yf169chung@cuhk.edu.hk, Wong, Sze-Ching³ (AUTHOR) scwong@cuhk.edu.hk, Chen, Hong⁶ (AUTHOR) cherrychen30@126.com, Woo, Peter Yat-Ming⁷ (AUTHOR) peterwoo@surgery.cuhk.edu.hk, Chan, Danny Tat-Ming⁷ (AUTHOR) tmdanny@surgery.cuhk.edu.hk, Mao, Ying^1,2 (AUTHOR) maoying@fudan.edu.cn, Ng, Ho-Keung^2,3 (AUTHOR) maoying@fudan.edu.cn

المصدر: Cancers. May2024, Vol. 16 Issue 9, p1740. 15p.

مصطلحات موضوعية: *GENE rearrangement, *LYMPHOMAS, *SYMPTOMS, *AGE distribution, *DESCRIPTIVE statistics, *GENE expression, *GENE expression profiling, *FLUORESCENCE in situ hybridization, *GENETIC mutation, *PHENOTYPES, *HLA-B27 antigen, *IMMUNOMODULATORS, *SEQUENCE analysis, *CHILDREN, *ADULTS, CENTRAL nervous system tumors

مستخلص: Simple Summary: Primary CNS lymphomas (PCNSLs) in children and young adults are not common. In this study, we studied immunophenotype, gene rearrangement, homozygous deletion of CDKN2A and HLA, and mutation profiling of 34 PCNSL patients aged between 7 and 39 years and correlated the findings with clinical features and outcome. We found that the PCNSLs of the pediatric and young adult patients were immunophenotypically different from the PCNSLs of the older patients. They were also molecularly different from the latter group, as many of the common molecular findings identified in the latter were not present or common in the PCNSLs of the pediatric and young adult patients. Pediatric brain tumors are often noted to be different from their adult counterparts in terms of molecular features. Primary CNS lymphomas (PCNSLs) are mostly found in elderly adults and are uncommon in children and teenagers. There has only been scanty information about the molecular features of PCNSLs at a young age. We examined PCNSLs in 34 young patients aged between 7 and 39 years for gene rearrangements of BCl2, BCL6, CCND1, IRF4, IGH, IGL, IGK, and MYC, homozygous deletions (HD) of CDKN2A, and HLA by FISH. Sequencing was performed using WES, panel target sequencing, or Sanger sequencing due to the small amount of available tissues. The median OS was 97.5 months and longer than that for older patients with PCNSLs. Overall, only 14 instances of gene rearrangement were found (5%), and patients with any gene rearrangement were significantly older (p = 0.029). CDKN2A HD was associated with a shorter OS (p < 0.001). Only 10/31 (32%) showed MYD88 mutations, which were not prognostically significant, and only three of them were L265P mutations. CARD11 mutations were found in 8/24 (33%) cases only. Immunophenotypically, the cases were predominantly GCB, in contrast to older adults (61%). In summary, we showed that molecular findings identified in the PCNSLs of the older patients were only sparingly present in pediatric and young adult patients. [ABSTRACT FROM AUTHOR]

المؤلفون: Seto, Andrew¹ (AUTHOR) andrew.seto@uhn.ca, Downs, Gregory¹ (AUTHOR) gregory.downs@uhn.ca, King, Olivia¹ (AUTHOR) olivia.king@uhn.ca, Salehi-Rad, Shabnam¹ (AUTHOR) shabnam.salehi-rad@uhn.ca, Baptista, Ana¹ (AUTHOR) ana.baptista@uhn.ca, Chin, Kayu¹ (AUTHOR) kayu.chin@uhn.ca, Grenier, Sylvie¹ (AUTHOR) sylvie.grenier@uhn.ca, Nwachukwu, Bevoline¹ (AUTHOR) bev.nwachukwu@uhn.ca, Tierens, Anne^2,3 (AUTHOR) anne.tierens@uhn.ca, Minden, Mark D.⁴ (AUTHOR) mark.minden@uhn.ca, Smith, Adam C.^1,2 (AUTHOR) adam.smith@utoronto.ca, Capo-Chichi, José-Mario^1,2 (AUTHOR) adam.smith@utoronto.ca

المصدر: Cancers. May2024, Vol. 16 Issue 9, p1693. 19p.

مصطلحات موضوعية: *GENOMICS, *GENE rearrangement, *DNA, *DIAGNOSTIC errors, *GENE mapping, *CHROMOSOME banding, *FLUORESCENCE in situ hybridization, *GENE expression profiling, *SEQUENCE analysis, *GENETICS

مستخلص: Simple Summary: Genetic rearrangements of the KMT2A gene are associated with diagnostic and prognostic outcomes in the context of myeloid neoplasms. While cytogenetically visible KMT2A rearrangements (e.g., translocations) are relatively straightforward to detect by conventional cytogenetics, KMT2A partial tandem duplications (KMT2A-PTD) are too small to be detected by karyotype or FISH. Our study compares the detection of the KMT2A-PTD using three technologies: next-generation sequencing, multiplex-ligation probe amplification, and optical genome mapping. Background: Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (KMT2A-PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches. Methods: We have validated the use of a custom hybrid-capture-based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A. To deduce the presence of a KMT2A-PTD, we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM). Results: We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS, and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. The two false-positive KMT2A-PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with KMT2A-PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A, while MLPA yielded inconclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels. Conclusions: KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels, and OGM are complementary technologies applied in standard-of-care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results showed that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy-number-based KMT2A-PTD detection methodologies. [ABSTRACT FROM AUTHOR]

المؤلفون: Yin, Zhan¹ (AUTHOR), Kilkenny, Mairi L.¹ (AUTHOR), Ker, De‐Sheng¹ (AUTHOR), Pellegrini, Luca¹ (AUTHOR) lp212@cam.ac.uk

المصدر: FEBS Journal. Apr2024, Vol. 291 Issue 8, p1813-1829. 17p.

مصطلحات موضوعية: *RNA synthesis, *GENE rearrangement, *DNA polymerases, *DNA replication, *DNA synthesis, *STRUCTURAL dynamics, *DEOXYRIBOZYMES, *DNA primers

مستخلص: Eukaryotic DNA replication depends on the primosome – a complex of DNA polymerase alpha (Pol α) and primase – to initiate DNA synthesis by polymerisation of an RNA–DNA primer. Primer synthesis requires the tight coordination of primase and polymerase activities. Recent cryo‐electron microscopy (cryoEM) analyses have elucidated the extensive conformational transitions required for RNA primer handover between primase and Pol α and primer elongation by Pol α. Because of the intrinsic flexibility of the primosome, however, structural information about the initiation of RNA primer synthesis is still lacking. Here, we capture cryoEM snapshots of the priming reaction to reveal the conformational trajectory of the human primosome that brings DNA primase subunits 1 and 2 (PRIM1 and PRIM2, respectively) together, poised for RNA synthesis. Furthermore, we provide experimental evidence for the continuous association of primase subunit PRIM2 with the RNA primer during primer synthesis, and for how both initiation and termination of RNA primer polymerisation are licenced by specific rearrangements of DNA polymerase alpha catalytic subunit (POLA1), the polymerase subunit of Pol α. Our findings fill a critical gap in our understanding of the conformational changes that underpin the synthesis of the RNA primer by the primosome. Together with existing evidence, they provide a complete description of the structural dynamics of the human primosome during DNA replication initiation. [ABSTRACT FROM AUTHOR]

المؤلفون: Crepaldi, Tiziana^1,2 (AUTHOR) tiziana.crepaldi@unito.it, Gallo, Simona^1,2 (AUTHOR) simona.gallo@unito.it, Comoglio, Paolo Maria³ (AUTHOR) pcomoglio@gmail.com

المصدر: Pharmaceuticals (14248247). Apr2024, Vol. 17 Issue 4, p448. 15p.

مصطلحات موضوعية: *HEPATOCYTE growth factor, *GENE rearrangement, *CANCER cell proliferation, *CANCER remission, *PROTEIN-tyrosine kinases, *ONCOGENES, *GENE amplification

مستخلص: The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy. [ABSTRACT FROM AUTHOR]