Статті в журналах: "LZTR1"

1

Steklov, M., S. Pandolfi, M. F. Baietti, A. Batiuk, P. Carai, P. Najm, M. Zhang, et al. "Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination." Science 362, no. 6419 (November 15, 2018): 1177–82. http://dx.doi.org/10.1126/science.aap7607.

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The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

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2

Ko, Aram, Mohammad Hasanain, Young Taek Oh, Fulvio D'Angelo, Danika Sommer, Brulinda Frangaj, Suzanne Tran, et al. "CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii38. http://dx.doi.org/10.1093/neuonc/noac209.150.

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Abstract LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.

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3

Chen, Sisi, Rahul S. Vedula, Pau Castel, Antonio Cuevas Navarro, Simon J. Hogg, Eric Wang, Xiaoli Mi, et al. "Impaired RAS Proteolysis Drives Clonal Hematopoietic Transformation." Blood 138, Supplement 1 (November 5, 2021): 356. http://dx.doi.org/10.1182/blood-2021-147026.

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Abstract Recently, the protein LZTR1 (leucine zipper-like transcriptional regulator 1) was discovered as an adaptor for a cullin 3 complex responsible for ubiquitin-mediated degradation of RAS proteins. While these data provided a novel mechanism for RAS protein regulation, there is considerable controversy as to which RAS paralogs are physiologic substrates of LZTR1. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations in both LZTR1 as well as the RAS GTPase and LZTR1 substrate RIT1 were identified in patients with clonal hematopoietic disorders. However, the effects of these alterations on normal and maliganant hematopoiesis have not been evaluated. Here we utilized a series of genetically engineered murine models for germline and conditional deletion of LZTR1, RIT1, and expression of oncogenic RIT1 mutant which revealed a key role for LZTR1 in the regulation of hematopoietic stem cell (HSC) self-renewal and delineated a series of LZTR1-regulated substrates in hematopoietic cells. Consistent with a role for LZTR1 alterations in the Noonan Syndrome, germline homozygous deletion of Lztr1 was associated with lethality between embryonic day 17.5 and birth. Lztr1-/- fetuses had massive dyserythropoiesis and apoptosis of fetal liver hematopoietic cells. Competitive transplantation of E14.5 Lztr1 null fetal liver or bone marrow from 6-week-old Mx1-cre Lztr1 conditional knockout (cKO) mice resulted in striking increased self-renewal in primary and secondary competitive transplantation assays in vivo (Fig.A-B). Interestingly, recipient animals reconstituted with Lztr1-/- cells developed fatal myeloid and lymphoid leukemias characterized by anemia, thrombocytopenia, and increased myeloid and B-lymphoid cells (Fig.C-D). In order to identify the LZTR1 substrates responsible for effects on HSCs, we evaluated levels of all RAS GTPases in Lztr1 null HSCs. This revealed elevated KRas, NRas, MRas, and Rit1 protein in LZTR1 KO cells (Fig.E), with RIT1 being most prominently elevated. Evaluation of a cohort of 4,113 patients with hematologic malignancies identified 41 patients with somatic RIT1 mutations, the majority of which cluster in the switch II region and escape LZTR1-mediated ubiquitination, resulting in RIT1 protein accumulation (Fig.F-H). Given that the impact of RIT1 mutations on hematopoiesis is unknown, we next compared Lztr1 cKO with conditional expression of one of the most common leukemia-associated RIT1 mutants that escapes LZTR1-mediated ubiquitin (Rit1 M90I). Both Lztr1 cKO and Rit1 M90I conditional expression conferred GM-CSF hypersensitivity to HSCs in vitro, cytokine independent growth to human AML cell lines in vitro, and strong competitive self-renewal in vivo (Fig. I-J). Consistent with RIT1 mutations being found primarily in myeloid neoplasm patients, aged Mx1-cre Rit1M90I/WT mice developed fatal MPN, MDS, and mixed MDS/MPN disorders (Fig.K), which were serially transplantable into sublethally irradiated recipients. Despite convergent effects of LZTR1 and RIT1 on clonal HSC advantage, LZTR1 null cell lines did not solely require RIT1 for HSC advantage as revealed by Lztr1/Rit1 double KO mice. We therefore next carried out a series of experiments in RAS-less cells and whole genome CRISPR screens to delineate factors required for LZTR1 mediated hematopoietic transformation. This revealed that KRAS as well as MRAS and its RAF phosphatase partner SHOC2 were selective dependencies for LZTR1-mediated transformation. These data indicate that multiple RAS GTPases as well as RAF activation are required for LZTR1-mediated transformation (Fig.L). While considerable prior research has evaluated oncogenic alleles of RAS which alter RAS-GTP hydrolysis on hematopoiesis, the role of modulating RAS protein abundance on hematopoiesis is unknown. Here we identify RAS proteolysis as a novel regulator of HSC function, define the spectrum of RIT1 mutations in leukemia, and identify LZTR1 and RIT1 mutations as drivers of leukemogenesis. The discovery of RAS proteolysis as a novel driver of leukemogenesis has important therapeutic implications given efforts to therapeutically degrade RAS family members. Finally, the clinical importance of K/NRAS mutations on resistance to therapies in AML motivates future studies on the potential clinical impact of LZTR1 and RIT1 alterations in myeloid neoplasm patients. Figure 1 Figure 1. Disclosures Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Merck: Consultancy; Foundation Medicine Inc: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees.

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4

Song, Xuemin, Dongming Luo, Qian Zhong, Ke Wei, Yangyang Tang, Dongbo Wu, Junyi Xu, and Pengcheng Yu. "Effect of Targeting Leucine-Zipper-Like Transcription Regulator 1 Gene on Colon Cancer Cells." Journal of Biomaterials and Tissue Engineering 11, no. 8 (August 1, 2021): 1588–94. http://dx.doi.org/10.1166/jbt.2021.2727.

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LZTR1 is associated with several diseases, including liver cancer, childhood cancer, and schwannomas. However, LZTR1’s role in colon cancer and its mechanism of action have not been reported. The colon cancer tissues and adjacent tissues were collected to measure the expression of LZTR1 by Real time PCR. Colon cancer SW620 cell lines were cultured and randomly divided into control group and LZTR1 group followed by analysis of LZTR1 expression by real time PCR, cell proliferation by MTT assay, Caspase3 activity, Bcl-2 and Bax level by Real time PCR, cell invasion by Transwell chamber; NF-κB/VEGF expression by Western blot. LZTR1 expression was significantly reduced in colon cancer tissues compared to adjacent tissues (P <0.05) and negatively correlated with colon cancer TNM stage, tumor size, and lymph node metastasis, and positively associated with tumor differentiation (P <0.05). LZTR1 plasmid transfection into SW620 cells can significantly up-regulate LZTR1, inhibit tumor cell proliferation and invasion, increase Caspase 3 activity and Bax level, downregulate Bcl-2, NF-κB and VEGF (P <0.05). LZTR1 expression is reduced in colon cancer tissues, which is related to its clinicopathological characteristics. Up-regulation of LZTR1 can regulate apoptosis and inhibit tumor proliferation and invasion by regulating NF-κB/VEGF signaling pathway.

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5

Zhou, Bo, Xinyu Ying, Yingcong Chen, and Xingchen Cai. "A Comprehensive Pan-Cancer Analysis of the Tumorigenic Effect of Leucine-Zipper-Like Transcription Regulator (LZTR1) in Human Cancer." Oxidative Medicine and Cellular Longevity 2022 (October 17, 2022): 1–19. http://dx.doi.org/10.1155/2022/2663748.

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The elucidation of the action site, mechanism of Leucine-Zipper-like Transcription Regulator-1 (LZTR1) and its relationship with RAS-MAPK signaling pathway attracts more and more scholars to focus on the researches of LZTR1 and its role in tumorigenesis. However, there was no pan-cancer analysis between LZTR1 and human tumors reported before. Therefore, we are the first to investigate the potential oncogenic roles of LZTR1 across all tumor types based on the datasets of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus). LZTR1 plays a double-edged role in tumor development and prognosis. We found that the high expression of LZTR1 brings better outcomes in esophageal carcinoma (ESCA) and head and neck squamous cell carcinoma (HNSC) but brings worth outcomes in uveal melanoma (UVM), adrenocortical carcinoma (ACC), liver hepatocellular carcinoma (LIHC), and prostate adenocarcinoma (PRAD). Moreover, the expression of LZTR1 also strongly associated with pathological in ACC and bladder urothelial carcinoma (BLCA). We also found that the LZTR1 expression was associated with some immune cell infiltration including endothelial cells, regulatory T cells (Tregs), T cell CD8+, natural killer cells (NK cell), macrophages, neutrophil granulocyte, and cancer-associated fibroblasts in different cancers. Missense mutation in LZTR1 was detected in most cancers from TCGA datasets. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Body (GO) method was used to explain the pathogenesis of LZTR1. Our pan-cancer study provides a relatively comprehensive understanding of the carcinogenic role of LZTR1 in human tumors.

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6

Inoue, Daichi, Jacob T. Polaski, Justin Taylor, Pau Castel, Sisi Chen, Susumu Kobayashi, Simon J. Hogg, et al. "ZRSR2 Mutation Induced Minor Intron Retention Drives MDS and Diverse Cancer Predisposition Via Aberrant Splicing of LZTR1." Blood 136, Supplement 1 (November 5, 2020): 10–11. http://dx.doi.org/10.1182/blood-2020-136445.

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Mutations in RNA splicing factors are amongst the most common genetic alterations in myeloid malignancies. Mutations in the splicing factors SF3B1, SRSF2, and U2AF1 occur as heterozygous, missense mutations and have been shown to confer a change-of-function. In contrast, the X chromosome encoded ZRSR2 is enriched in nonsense/frameshift mutations in males, consistent with loss of function. To date however, we do not understand the basis for enrichment of ZRSR2 mutations in leukemia. Moreover, ZRSR2 is the only one of these factors that primarily functions in the minor spliceosome. While most introns are spliced by the major spliceosome, a small subset (<1%) of introns are recognized by a separate complex, the minor spliceosome. Although minor (or "U12") introns are present in only ~800 genes in humans, their sequences and positions are highly evolutionarily conserved - more so than their U2 counterparts. The high conservation of minor introns suggests key regulatory roles yet few functional roles for the minor spliceosome in regulating biological phenotypes are known. The rarity and conservation of minor introns offered a unique opportunity to investigate splicing factor mutations and identify potential tissue-specific roles of the minor spliceosome. Modeling loss-of-function mutations in ZRSR2 via a mouse model for induced deletion of Zrsr2 revealed strikingly enhanced self-renewal of Zrsr2-deficient male and female hematopoietic cells (Fig. A-C). This was in stark contrast to the effects of hotspot mutations in Sf3b1and Srsf2 and similar to those of Tet2 loss on increasing self-renewal and numbers of HSCs. Zrsr2 loss was also associated increased myeloid cells in the blood and long-term hematopoietic stem cells (HSCs) in the marrow (Fig. C). To understand the mechanistic basis by which ZRSR2 loss causes aberrant HSC self-renewal, we quantified transcriptome-wide splicing patterns in MDS patients. ZRSR2-mutant samples had widespread, dysfunctional recognition of minor introns- 48% of minor introns exhibiting significantly increased retention (Fig. D). We next systematically mimicked the effects of nonsense-mediated decay caused by minor intron retention in ZRSR2-mutants. Every gene containing a ZRSR2-regulated minor intron was targeted by 4 sgRNAs via a positive-enrichment CRISPR screen using pools of lentiviral sgRNAs in cytokine-dependent human and mouse hematopoietic cell lines. This identified several minor intron-containing genes whose downregulation conferred cytokine independence. Strikingly, just one gene was enriched in all lines (Fig. E): LZTR1, a cullin-3 adaptor for ubiquitin-mediated suppression of RAS-related GTPases which is subject to loss-of-function mutations in several cancers and the RASopathy Noonan Syndrome. Minor intron retention in LZTR1 correlated with reduced LZTR1 protein in MDS patients (Fig. F-G). Inducing mutations in either the protein-coding region of LZTR1 or its minor intron resulted in cytokine independence (Fig. H), reduced LZTR1, and dramatic accumulation of RIT1, a RAS GTPase substrate of LZTR1. In a Noonan Syndrome family wherein one child died of AML, the mother and all children carried an intronic mutation within LZTR1's minor intron (Fig. I-J). Fibroblasts from each family member revealed clear LZTR1 minor intron retention with impaired LZTR1 protein expression and RIT1 accumulation in subjects bearing the LZTR1 minor intron mutation (Fig. J). We next interrogated LZTR1 minor intron splicing across all cancers in the TCGA. While LZTR1's minor intron was efficiently excised in normal samples, a notable subset of tumors in almost all cancer types exhibited significantly increased retention within LZTR1's minor intron. These data indicate LZTR1 is frequently dysregulated via perturbed minor intron splicing - much more so than by protein-coding mutations alone. Here we uncover a heretofore unrecognized role of minor intron excision in regulating HSC self-renewal, a molecular link between ZRSR2 mutations and aberrant LZTR1 splicing and expression, and frequent LZTR1 minor intron retention in diverse cancers and cancer predisposition syndromes. Given frequent post-transcriptional disruption of LZTR1 in the absence of protein-coding mutations, our data additionally motivate study of other cancer-associated minor intron-containing genes which may be dysregulated via similar, and as-yet-undetected, aberrant splicing. Figure Disclosures Abdel-Wahab: Merck: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding; Janssen: Consultancy.

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Smith, Miriam J., Naomi L. Bowers, Michael Bulman, Carolyn Gokhale, Andrew J. Wallace, Andrew T. King, Simon K. L. Lloyd, et al. "Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis." Neurology 88, no. 1 (November 16, 2016): 87–92. http://dx.doi.org/10.1212/wnl.0000000000003418.

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Objective:To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors.Methods:We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas.Results:Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation.Conclusions:The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.

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Bigenzahn, Johannes W., Giovanna M. Collu, Felix Kartnig, Melanie Pieraks, Gregory I. Vladimer, Leonhard X. Heinz, Vitaly Sedlyarov, et al. "LZTR1 is a regulator of RAS ubiquitination and signaling." Science 362, no. 6419 (November 15, 2018): 1171–77. http://dx.doi.org/10.1126/science.aap8210.

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In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of theDrosophila LZTR1orthologCG3711resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation ofLZTR1led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. BecauseLZTR1disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale forLZTR1involvement in a variety of inherited and acquired human disorders.

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Mansouri, Sheila, Suganth Suppiah, Yasin Mamatjan, Irene Paganini, Jeff Liu, Shirin Karimi, Vikas Patil, et al. "EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS." Neuro-Oncology 22, Supplement_2 (November 2020): ii69—ii70. http://dx.doi.org/10.1093/neuonc/noaa215.283.

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Abstract Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.

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Castel, Pau, Alice Cheng, Antonio Cuevas-Navarro, David B. Everman, Alex G. Papageorge, Dhirendra K. Simanshu, Alexandra Tankka, Jacqueline Galeas, Anatoly Urisman, and Frank McCormick. "RIT1 oncoproteins escape LZTR1-mediated proteolysis." Science 363, no. 6432 (March 14, 2019): 1226–30. http://dx.doi.org/10.1126/science.aav1444.

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RIT1 oncoproteins have emerged as an etiologic factor in Noonan syndrome and cancer. Despite the resemblance of RIT1 to other members of the Ras small guanosine triphosphatases (GTPases), mutations affecting RIT1 are not found in the classic hotspots but rather in a region near the switch II domain of the protein. We used an isogenic germline knock-in mouse model to study the effects of RIT1 mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, we detected a RIT1 interactor, leucine zipper–like transcription regulator 1 (LZTR1), that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Our results highlight a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1.

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11

Bianchessi, Donatella, Maria Cristina Ibba, Veronica Saletti, Stefania Blasa, Tiziana Langella, Rosina Paterra, Giulia Anna Cagnoli, et al. "Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients." Genes 11, no. 6 (June 19, 2020): 671. http://dx.doi.org/10.3390/genes11060671.

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Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.

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Jacquinet, Adeline, Adeline Bonnard, Yline Capri, Didier Martin, Bernard Sadzot, Elettra Bianchi, Laurent Servais, Jean-Paul Sacré, Hélène Cavé, and Alain Verloes. "Oligo-astrocytoma in LZTR1-related Noonan syndrome." European Journal of Medical Genetics 63, no. 1 (January 2020): 103617. http://dx.doi.org/10.1016/j.ejmg.2019.01.007.

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Umeki, Ikumi, Tetsuya Niihori, Taiki Abe, Shin-ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, et al. "Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1–PPP1CB complexes." Human Genetics 138, no. 1 (October 27, 2018): 21–35. http://dx.doi.org/10.1007/s00439-018-1951-7.

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Paganini, Irene, Vivian Y. Chang, Gabriele L. Capone, Jeremie Vitte, Matteo Benelli, Lorenzo Barbetti, Roberta Sestini, et al. "Expanding the mutational spectrum of LZTR1 in schwannomatosis." European Journal of Human Genetics 23, no. 7 (October 22, 2014): 963–68. http://dx.doi.org/10.1038/ejhg.2014.220.

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Abe, Taiki, Ikumi Umeki, Shin-ichiro Kanno, Shin-ichi Inoue, Tetsuya Niihori, and Yoko Aoki. "LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases." Cell Death & Differentiation 27, no. 3 (July 23, 2019): 1023–35. http://dx.doi.org/10.1038/s41418-019-0395-5.

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Eoli, M. E., D. Bianchessi, M. Moscatelli, L. Chiapparini, C. Ibba, G. Finocchiaro, and M. Bruzzone. "OS2.3 Relevance of Neurofibromatosistype 1 and schwannomotosis in extramedullary spine tumors." Neuro-Oncology 21, Supplement_3 (August 2019): iii8. http://dx.doi.org/10.1093/neuonc/noz126.023.

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Abstract BACKGROUND Extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas and neurofibromatosis or schwannomatosis can be suspected. Given the rarity of this condition the clinical genetic and radiological features remains to be better define. The aim of this study was to characterize the clinical, radiologic presentation of patients with widespread spinal disease and to identify gene mutation. MATERIAL AND METHODS We selected patient with a at least: intradural extramedullary, or extradural intraspinal (tumor within the spinal canal), or extradural paraspinal (tumor at the neural foramenor extending outward into adjacent tissues) neoplasms and no other tumors such as meningiomas in the spine at spine MRI. Patients’ DNA were analyzed by Targeted NGS by means a custom gene panel including NF1, NF2, LZTR1, SMARCB1 genes. RESULTS 63 patients were identified31 had few isolated tumors, involving spinal roots (Multiple Neurofibromas Few Spinal Root, MNFSR), 18 had bilateral neurofibromas involving all spinal roots. 14 had a single lesion; 10 cases were familiar and 53 sporadic. Genetic analysis showed NF1 gene mutations (in prevalence splicing or missense) in 49 cases LZTR1 mutations in 3 and in the others 11 no mutation or deletion was detected. Pain was the hallmark symptom in patients with LZTR1 mutations, while all familial cases all had NF1 diagnosis. About 50% of them had few cutaneous manifestations. CONCLUSION In patients with extramedullary spine tumors is important to look for signs of neurofibromatosis or schawannomatosis and if there are present genetic testing should be performed.

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Nogué, Clara, Anne-Sophie Chong, Elia Grau, HyeRim Han, Eduard Dorca, Carla Roca, Jose Luis Mosquera, et al. "Abstract 1549: The tumorigenesis model in DGCR8 associated schwannomatosis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1549. http://dx.doi.org/10.1158/1538-7445.am2022-1549.

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Abstract Purpose: Schwannomatosis is an inherited disorder that affects Schwann cells from peripheral nerves. It is diagnosed when multiple schwannomas occur in the absence of bilateral vestibular schwannomas. The two main genes associated with this disorder are SMARCB1 and LZTR1 both on chromosome 22q (Chrm22q). Somatic inactivation of NF2, downstream of SMARCB1, is observed in most schwannomas. The accepted model of schwannomatosis involves multiple hits over three steps to inactivate LZTR1 or SMARCB1 together with NF2. Following this pattern, most of the LZTR1/SMARCB1-schwannomas acquire a somatic loss of Chrm22 (thus deleting the three genes) and a somatic mutation affecting the remaining wild-type NF2 copy on the GPV allele. Several studies have postulated the plausible existence of other susceptibility genes predisposing to schwannomatosis and the likelihood of those being localized in Chrm22q. Last year we identified a GPV in the microprocessor DGCR8 (c.1552G>A; p.E518K) located in the Chrm22q11 region, as responsible for a familial form of schwannomatosis and multinodular goiter (Rivera et al JCI, 2020). Our goal is to clarify the role of DGCR8 as a novel tumor susceptibility gene and the tumorigenic mechanisms that lead to DGCR8-schwannomatosis. Methods: We searched for patients affected of schwannoma and thyroid tumors. By whole exome sequencing we identified the same DGCR8 (c.1552G>A; p.E518K) variant in one patient. We then collected a total of 13 DGCR8-schwannomas from carriers. Eleven tumors were subjected to WES and two tumors were subjected to a NGS targeted panel covering all known schwannoma genes in Chrm22q. Results: We report the second case of a patient with peripheral schwannomatosis and thyroid alterations caused by the germline pathogenic variant E518K in DGCR8. Loss of Chrm22q was seen in all 13 tumors analyzed. While all tumors had at least one alteration of NF2, 4 tumors had no somatic mutations on the retained (not deleted) allele (30.8%). Given that DGCR8 localizes 5’ of LZTR1, the second step (LOH) leads to the deletion of DGCR8 and the three bona fide schwannoma genes (LZTR1, SMARCB1 and NF2) adding up to a total of 6 hits in a 3-step model. Suggesting that the path to tumorigenesis driven by DGCR8 requires the loss of the wild type allele of Chrm22q and in more than two thirds of the tumors a complete inactivation of NF2 occurs. Conclusion: Our findings highlight DGCR8 as a schwannomatosis gene mapping to the Chrm22 cluster of tumor suppressors that cooperate to promote tumorigenesis in Schwann cell and pinpoints an important role of miRNA regulation in this process. Citation Format: Clara Nogué, Anne-Sophie Chong, Elia Grau, HyeRim Han, Eduard Dorca, Carla Roca, Jose Luis Mosquera, Conxi lazaro, William D. Foulkes, Joan Brunet, Bárbara Rivera Polo. The tumorigenesis model in DGCR8 associated schwannomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1549.

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Wei, Wei, Mitchell Geer, Xinyi Guo, Neville Sanjana, and Benjamin G. Neel. "Abstract 659: Mechanisms of resistance to SHP2 inhibition." Cancer Research 82, no. 12_Supplement (June 15, 2022): 659. http://dx.doi.org/10.1158/1538-7445.am2022-659.

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Abstract SHP2 (PTPN11) is required for RAS activation, acting upstream of SOS1/2. Allosteric SHP2 inhibitors (SHP2is) stabilize auto-inhibition mediated by N-SH2/PTP interactions and prevent its activation by upstream stimuli. SHP2is impair the proliferation of oncogenic RTK- or cycling RAS mutant-expressing tumor cells and can overcome adaptive resistance to single agents targeting the RAS-MAPK-ERK pathway (e.g., EGFR, KRASG12C, BRAFV600E, MEK inhibitors). Multiple SHP2is are in clinical trials as single agents or in various combinations. As resistance to targeted therapy is universal, we sought to prospectively identify potential SHP2-extrinsic resistance mechanisms by performing genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive human FLT3-ITD driven AML cell lines, MOLM13 and MV4:11. We identified several expected “hits” based on known signaling pathways, including tumor suppressor (NF1, PTEN,CDKN1B) and “RASopathy” (LZTR1, RASA2) genes, as well as novel targets including INPPL1,MAP4K5, and some epigenetic modifiers. To test the generality of these findings, we built a“mini-CRISPR library of ~30 hits common to MOLM13 and MV4:11 cells and screened 15 SHP2i-sensitive lines. LZTR1 deletion conferred resistance in 14/15, followed by MAP4K5 (9/15),SPRED2 (6/15), STK40 (6/15), INPPL1 (5/15), NCOA6 (4/15), NCOR1 (4/15), and ELAVL1 (4/15). LZTR1 has been reported to regulate RIT or RAS stability. Notably, LZTR1 knockout universally increased RIT1, but in some lines, also increased RAS. INPPL1 encodes SHIP2, a 5’-inositide phosphatase that negatively regulates AKT activation in insulin signaling. However, INPPL1 deletion also increased RAS and ERK activity and activated ERK-dependent genes in FLT3-ITD AML lines. Experiments with INPPL1 mutant showed that SHC binding and an N-terminal region, but not the SH2 domain or phosphatase activity, is required for negative regulation of RAS. Interestingly, INPPL1 deletion also promoted resistance to SHP2 inhibition in several EGFR mutant cell lines. MAP4K5 deletion also increased ERK-dependent gene expression. Kinase activity, but not JNK activation, was required for MAP4K5 action. Our results predict multiple mechanisms of SHP2i resistance, emphasizing the need for detailed understanding of the resistance landscape to arrive a combinations that provide long term disease control. Citation Format: Wei Wei, Mitchell Geer, Xinyi Guo, Neville Sanjana, Benjamin G. Neel. Mechanisms of resistance to SHP2 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 659.

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Johnston, Jennifer J., Jasper J. van der Smagt, Jill A. Rosenfeld, Alistair T. Pagnamenta, Abdulrahman Alswaid, Eva H. Baker, Edward Blair, et al. "Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants." Genetics in Medicine 20, no. 10 (February 22, 2018): 1175–85. http://dx.doi.org/10.1038/gim.2017.249.

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Basenach, Elena, Alisa Förster, Peter Raab, Samer Alzein, Gunnar Schmidt, Joachim Krauss, Fedor Heidenreich, et al. "INNV-06. TREATMENT RESPONSE TO BEVACIZUMAB OVER TWO YEARS IN A PATIENT WITH GENETICALLY PROVEN SOMATIC NEUROFIBROMATOSIS TYPE 2 MOSAICISM." Neuro-Oncology 21, Supplement_6 (November 2019): vi131. http://dx.doi.org/10.1093/neuonc/noz175.549.

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Abstract Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by the development of schwannomas, especially bilateral vestibular schwannomas (VS), and meningiomas. Heterozygous pathogenic variants in the NF2 gene are known to cause NF2, whereby somatic mosaicism is present in ~25% of simplex patients. In schwannomatosis, a disorder phenotypically similar to NF2, heterozygous SMARCB1 or LZTR1 variants may be causative. Recently, bevacizumab has shown efficiency as therapy for VS in some NF2 patients. We report on a thirty-three-year-old patient with bilateral VS, fourteen additional schwannomas and one intracranial meningioma. Next generation sequencing using a cancer gene panel and Sanger sequencing of LZTR1 on blood and oral mucosa DNA revealed no pathogenic variants in NF2, SMARCB1 or LZTR1. Sanger sequencing on DNA from three schwannomas identified the known NF2 nonsense variant c.784C >T;p.(R262*) (NM_000268.3, GRCh37/hg19) in all tumors, leading to the diagnosis of somatic NF2 mosaicism. Because of hearing impairment and tumor progression the patient underwent an off-label therapy with 5mg/kg bevacizumab. To determine treatment response, we evaluated MRI scans from five pre-therapeutic and two therapeutic years as well as pure-tone audiometry. After 25 months of treatment, (i) the pure-tone average improved by 11.2 dB indicating a hearing benefit, (ii) four of seven non-vestibular schwannomas showed a volume reduction of ≥ 20%, (iii) the volume of three of seven schwannomas stabilized, and (iv) the growth rate of the meningioma decreased. In conclusion, in a patient with somatic NF2 mosaicism, an off-label therapy with bevacizumab was efficient with respect to hearing improvement and tumor shrinkage in over half of non-vestibular schwannomas over a period of two years.

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Hanses, Ulrich, Mandy Kleinsorge, Lennart Roos, Gökhan Yigit, Yun Li, Boris Barbarics, Ibrahim El-Battrawy, et al. "Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome–Associated Cardiomyopathy." Circulation 142, no. 11 (September 15, 2020): 1059–76. http://dx.doi.org/10.1161/circulationaha.119.044794.

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Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS–mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. Methods: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 ( LZTR1 ). We generated induced pluripotent stem cell–derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. Results: Patients’ induced pluripotent stem cell–derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS–mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell–derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

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Mansouri, Sheila, Suganth Suppiah, Yasin Mamatjan, Irene Paganini, Jeffrey C. Liu, Shirin Karimi, Vikas Patil, et al. "Epigenomic, genomic, and transcriptomic landscape of schwannomatosis." Acta Neuropathologica 141, no. 1 (October 6, 2020): 101–16. http://dx.doi.org/10.1007/s00401-020-02230-x.

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AbstractSchwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

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Smith, M. J., B. Isidor, C. Beetz, S. G. Williams, S. S. Bhaskar, W. Richer, J. O'Sullivan, et al. "Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis." Neurology 84, no. 2 (December 5, 2014): 141–47. http://dx.doi.org/10.1212/wnl.0000000000001129.

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Güemes, María, Álvaro Martín-Rivada, Neimar Valentina Ortiz-Cabrera, Gabriel Ángel Martos-Moreno, Jesús Pozo-Román, and Jesús Argente. "LZTR1: Genotype Expansion in Noonan Syndrome." Hormone Research in Paediatrics 92, no. 4 (2019): 269–75. http://dx.doi.org/10.1159/000502741.

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Chinton, Josefina, Victoria Huckstadt, Mafalda Mucciolo, Francesca Lepri, Antonio Novelli, Luis Pablo Gravina, and María Gabriela Obregon. "Providing more evidence on LZTR1 variants in Noonan syndrome patients." American Journal of Medical Genetics Part A 182, no. 2 (December 11, 2019): 409–14. http://dx.doi.org/10.1002/ajmg.a.61445.

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Pagnamenta, Alistair T., Pamela J. Kaisaki, Fenella Bennett, Emma Burkitt‐Wright, Hilary C. Martin, Matteo P. Ferla, John M. Taylor, et al. "Delineation of dominant and recessive forms of LZTR1 ‐associated Noonan syndrome." Clinical Genetics 95, no. 6 (April 3, 2019): 693–703. http://dx.doi.org/10.1111/cge.13533.

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Nakaguma, Marilena, Alexander A. L. Jorge, and Ivo J. P. Arnhold. "Noonan syndrome associated with growth hormone deficiency with biallelic LZTR1 variants." Genetics in Medicine 21, no. 1 (June 30, 2018): 260. http://dx.doi.org/10.1038/s41436-018-0041-5.

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Mehta, Gautam U., Michael J. Feldman, Herui Wang, Dale Ding, and Prashant Chittiboina. "Unilateral vestibular schwannoma in a patient with schwannomatosis in the absence of LZTR1 mutation." Journal of Neurosurgery 125, no. 6 (December 2016): 1469–71. http://dx.doi.org/10.3171/2015.11.jns151766.

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The presence of vestibular schwannomas has long been considered an exclusion criterion for the diagnosis of schwannomatosis. Recently, 2 cases of vestibular schwannoma were reported in patients with schwannomatosis, leading to a revision of the diagnostic criteria for this genetic disorder. Overall, the relative infrequency of vestibular schwannomas in schwannomatosis is unexplained, and the genetics of this uncommon phenomenon have not been described. The authors report on a family with clinical manifestations consistent with schwannomatosis, including 4 affected members, that was identified as having an affected member harboring a unilateral cerebellopontine angle mass with extension into the internal auditory canal. Radiologically, this mass was consistent with a vestibular schwannoma and resulted in a symptomatic change in ipsilateral hearing (word recognition 86% at 52 dB) and increased latency of the wave I–V interval on auditory brainstem response testing. The patient was found to be negative for a germline mutation of NF2 and LZTR1, and her affected mother was found to harbor neither NF2 nor SMARCB1 mutations on genetic testing. Although vestibular schwannomas have been classically considered to not occur in the setting of schwannomatosis, this patient with schwannomatosis and a vestibular schwannoma further confirms that schwannomas can occur on the vestibular nerve in this syndrome. Further, this is the first such case found to be negative for a mutation on the LZTR1 gene.

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Evans, D. Gareth, Naomi L. Bowers, Simon Tobi, Claire Hartley, Andrew J. Wallace, Andrew T. King, Simon K. W. Lloyd, et al. "Schwannomatosis: a genetic and epidemiological study." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 11 (June 16, 2018): 1215–19. http://dx.doi.org/10.1136/jnnp-2018-318538.

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ObjectivesSchwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.MethodsSchwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available.ResultsRegional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).ConclusionsWithin the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

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Sewduth, Raj Nayan, Silvia Pandolfi, Mikhail Steklov, Aidana Sheryazdanova, Peihua Zhao, Nathan Criem, Maria F. Baietti, et al. "The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking." Circulation Research 126, no. 10 (May 8, 2020): 1379–93. http://dx.doi.org/10.1161/circresaha.119.315730.

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Gripp, K. W., L. Baker, V. Kandula, J. Piatt, A. Walter, Z. Chen, and L. Messiaen. "Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager." Clinical Genetics 92, no. 5 (April 19, 2017): 540–43. http://dx.doi.org/10.1111/cge.13013.

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Perin, Francesca, Juan Pablo Trujillo-Quintero, Juan Jimenez-Jaimez, María del Mar Rodríguez-Vázquez del Rey, Lorenzo Monserrat, and Luis Tercedor. "Two Novel Cases of Autosomal Recessive Noonan Syndrome Associated With LZTR1 Variants." Revista Española de Cardiología (English Edition) 72, no. 11 (November 2019): 978–80. http://dx.doi.org/10.1016/j.rec.2019.05.002.

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Morshed, Ramin, Anthony Lee, Young Lee, Cynthia Chin, and Line Jacques. "Schwannomatosis of the Spinal Accessory Nerve: A Case Report." Journal of Brachial Plexus and Peripheral Nerve Injury 14, no. 01 (January 2019): e9-e13. http://dx.doi.org/10.1055/s-0039-1685457.

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AbstractSchwannomatosis is a distinct syndrome characterized by multiple peripheral nerve schwannomas that can be sporadic or familial in nature. Cases affecting the lower cranial nerves are infrequent. Here, the authors present a rare case of schwannomatosis affecting the left spinal accessory nerve. Upon genetic screening, an in-frame insertion at codon p.R177 of the Sox 10 gene was observed. There were no identifiable alterations in NF1, NF2, LZTR1, and SMARCB1. This case demonstrates a rare clinical presentation of schwannomatosis in addition to a genetic aberration that has not been previously reported in this disease context.

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Hu, Yali, Xiangyu Zhu, Yuehua Yang, Xuming Mo, Min Sheng, Jincui Yao, and Dongjing Wang. "Incidences of micro-deletion/duplication 22q11.2 detected by multiplex ligation-dependent probe amplification in patients with congenital cardiac disease who are scheduled for cardiac surgery." Cardiology in the Young 19, no. 2 (April 2009): 179–84. http://dx.doi.org/10.1017/s1047951109003667.

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AbstractBackground22q11.2 microdeletion is the most common microdeletion in the global population. Congenital cardiac disease is the most frequently observed feature of this syndrome. The prognosis of patients with 22q11.2 copy number aberrations varies from those without 22q11.2 deletion or duplication.MethodsWe enrolled 241 patients from Nanjing Drum Tower Hospital and Nanjing Sick Children’s Hospital, 227 being scheduled for cardiac surgery, and 14 cases being fetuses aged from 24 to 36 gestational weeks. We performed karyotypic analysis and multiplex ligation-dependent probe amplification in all cases.ResultsKaryotypic analysis demonstrated 3 cases with trisomy 21, and 1 case with mosaic trisomy 8 [47,XY,+8/46,XY(1:2)]. Multiplex ligation-dependent probe amplification analysis revealed 10 cases (4.15%) with changes in the number of copies within the region of 22q11.2, of which 7 cases were hemizygous interstitial microdeletion from CLTCL1 to LZTR1, 1 case with deletion of the region from CLTCL1 to PCQAP, and 2 cases with 22q11.2 duplication, one of which spanned from ZNF74 to LZTR1, and simultaneously showed trisomy 21 by karyotyping analysis, and the other spanned from HIC2 to TOP3B. The phenotypes of the cardiac lesions included 3 cases of ventricular septal defect, 3 of tetralogy of Fallot, 2 of combined ventricular and atrial septal defects, and 2 with pulmonary arterial stenosis.ConclusionsPatients with congenitally malformed hearts who are scheduled for cardiac surgery, as well as fetuses with congenital cardiac disease, should routinely undergo karyotypic analysis and examination for 22q11.2 aberrations. Multiplex ligation-dependent probe amplification has been proven to be a cost-effective diagnostic technique for 22q11 deletion syndrome.

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Damnernsawad, Alisa, Tamilla Nechiporuk, Daniel Bottomly, Stephen E. Kurtz, Christopher A. Eide, Shannon K. McWeeney, and Jeffrey W. Tyner. "Genome-Wide CRISPR Screening Identifies MAPK and Mtorc Pathways As Regulators of Sorafenib Resistance in Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2557. http://dx.doi.org/10.1182/blood-2019-128877.

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Acute myeloid leukemia (AML) is a fast progressing blood malignancy with impaired differentiation and proliferation of myeloid precursors. It is one of the most common leukemias in adults and is known for its molecular and biological heterogeneity, with a variety of genetic lesions implicated in the disease. Among these variants, internal tandem duplication (ITD) or point mutations in the tyrosine kinase domain (TKD) of FLT3 tyrosine kinase are found in around 30% of AML patients. Sorafenib, a multi-kinase inhibitor that targets FLT3, RAF, VEGFR, FGFR, KIT and RET, is approved for use in hepatocarcinoma, renal cell carcinoma, and thyroid carcinoma treatments. Addition of different FLT3 inhibitors such as sorafenib to standard-of-care chemotherapy treatment prolongs AML patient survival with or without FLT3 mutations, although relapse caused by drug resistance remains a clinical challenge. Understanding the mechanisms of resistance to FLT3-targeted drugs, therefore, is necessary to improve treatment options and patient outcomes in AML. We aimed to elucidate resistance mechanisms to sorafenib by subjecting MOLM13 AML cells to genome-wide CRISPR screening to identify genes whose loss-of-function contributes to reduced drug sensitivity. Using Mageck along with an internally developed tiering system for screen hit prioritization, we identified negative regulators of MAPK as well as mTOR pathways as main players in sorafenib resistance. We validated prioritized hit genes using individual sgRNAs to generate single gene deficient cell models for LZTR1, NF1, TSC1 or TSC2. Drug sensitivity assays confirmed an increase in sorafenib resistance in these knockout cells. LZTR1-, TSC1- or TSC2-deficient cells also exhibited reduced sensitivity to a panel of additional FLT3 inhibitors. RNA sequencing results from 271 AML patient peripheral blood or bone marrow samples revealed a correlation between sorafenib sensitivity and lower expression of LZTR1, NF1, TSC1, and TSC2. MOLM13 cell lines resistant to crenolanib, quizartinib, and sorafenib were independently generated by incremental increase in concentration of each drug in cell culture media. Similarly, western blot analysis demonstrated up-regulation of MAPK and/or mTORC1 activity in these resistant cell lines. In addition, these cells were sensitive to MEK inhibitors, and the combination of FLT3 + MEK inhibitors showed synergistic efficacy over single agents in both resistant and parental cells. Taken together, our work identifies the contribution of the MAPK and PI3K/mTOR pathways to FLT3 inhibitor resistance in AML and suggests the combination of FLT3 + MEK inhibitors may be effective for AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors. Disclosures Tyner: Aptose: Research Funding; Array: Research Funding; Agios: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Syros: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Array: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Syros: Research Funding; Aptose: Research Funding; Petra: Research Funding; Seattle Genetics: Research Funding; Petra: Research Funding; Constellation: Research Funding; AstraZeneca: Research Funding; Agios: Research Funding.

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Chen, Yunjia, Alicia Gomes, Juan Dong, and Ludwine Messiaen. "eP330: Mosaicism for SMARCB1 or LZTR1 variants in patients with schwannomatosis in the UAB cohort." Genetics in Medicine 24, no. 3 (March 2022): S206—S207. http://dx.doi.org/10.1016/j.gim.2022.01.365.

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Oiso, Naoki, Kazuko Sakai, Tomohiko Narita, Shigeto Yanagihara, Kazuto Nishio, and Akira Kawada. "Lymph node metastatic melanoma from ungual melanoma: Identification of somatic mutations in KIT and LZTR1." Journal of Dermatology 45, no. 1 (September 25, 2017): e5-e6. http://dx.doi.org/10.1111/1346-8138.14071.

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Piotrowski, Arkadiusz, Jing Xie, Ying F. Liu, Andrzej B. Poplawski, Alicia R. Gomes, Piotr Madanecki, Chuanhua Fu, et al. "Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas." Nature Genetics 46, no. 2 (December 22, 2013): 182–87. http://dx.doi.org/10.1038/ng.2855.

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Barden, M., and J. Baehring. "P11.58.A Case of a complex neurocutaneous syndrome characterized by extensive peripheral nerve sheath tumors and somatic ERBB2 mutation." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii71. http://dx.doi.org/10.1093/neuonc/noac174.247.

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Abstract Schwannomatosis is a rare genetic tumor predisposition syndrome characterized by the presence of multiple non-intradermal schwannomas and the definitive absence of vestibular nerve involvement. Though considered benign, the burden of tumors can cause significant morbidity in the form of motor dysfunction and refractory neuropathic pain. Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab. Options for targeted medical therapies are lacking. Schwannomatosis is molecularly distinct from the other neurofibromatoses and by definition lacks constitutional mutations in NF1 and NF2. Instead, constitutional mutations in SMARCB1 or LZTR1 are often the “first hit” in tumorigenesis. Activating mutations in ERBB2 (also designated HER2) have been identified as oncogenic drivers in peripheral nerve sheath tumors in patients who lack these typical constitutional tumor suppressor gene mutations. Here we report a case of extensive peripheral nerve sheath tumors in the setting of apparent somatic mosaicism of an ERBB2 mutation. A 48-year-old man with history of chronic back pain presented with diffuse enlarging soft tissues masses primarily involving the left neck and occiput. Examination revealed areas of cutaneous heterogeneous hyperpigmentation, decreased muscle bulk and dorsiflexor weakness in the bilateral lower extremities, and steppage gait. Neuroimaging showed extensive T2 hyperintense, mildly enhancing masses within the bilateral thoracic and lumbar spine neuroforamina, intercostal nerves, paraspinal musculature, and lumbosacral plexus. Tissue from two separate tumor sites was morphologically consistent with schwannoma with some features of neurofibroma. Immunohistochemistry revealed partial loss of staining for SMARCB1. Whole exome sequencing (WES) on blood and tumor tissue did not show pathogenic germline or somatic variants for NF1, NF2, SMARCB1, LZTR1, or an array of tumor predisposition syndromes. WES on tumor tissue from both sites however did reveal a somatic ERBB2 variant (p.D769Y), suggesting mosaicism. ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.

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40

Barak, E. Cohen, H. Toledano-Alhadief, B. Mwassi, P. Sergei, M. Khayat, N. Danial-Farran, M. Ziv, and S. Shalev. "175 Concomitant LZTR1 and NF1 mutations contribute to the diversity of the Neurofibromatosis 1 phenotypic spectrum." Journal of Investigative Dermatology 141, no. 10 (October 2021): S178. http://dx.doi.org/10.1016/j.jid.2021.08.179.

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Paladino, Antonella, Fulvio D’Angelo, Teresa Maria Rosaria Noviello, Antonio Iavarone, and Michele Ceccarelli. "Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach." Journal of Chemical Information and Modeling 61, no. 4 (April 1, 2021): 1875–88. http://dx.doi.org/10.1021/acs.jcim.1c00296.

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Dragoš, Vita Šetrajčič, Ksenija Strojnik, Gašper Klančar, Petra Škerl, Vida Stegel, Ana Blatnik, Marta Banjac, Mateja Krajc, and Srdjan Novaković. "Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes." International Journal of Molecular Sciences 23, no. 13 (July 4, 2022): 7446. http://dx.doi.org/10.3390/ijms23137446.

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Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.

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Ruggieri, M., A. D. Praticò, A. Serra, L. Maiolino, S. Cocuzza, P. Di Mauro, L. Licciardello, et al. "ACTA OTORHINOLARYNGOLOGICA ITALICA." Acta Otorhinolaryngologica Italica 36, no. 5 (October 2016): 345–67. http://dx.doi.org/10.14639/0392-100x-1093.

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La neurofibromatosi tipo 2 [NF2] è una malattia genetica a trasmissione autosomica dominante [MIM # 101000]. Clinicamente è caratterizzata da: (1) schwannomi bilaterali del (VIII) nervo acustico/vestibolare; (2) cataratta giovanile o amartomi retinici; (3) schwannomi a carico dei nervi periferici e dei nervi cranici; (4) tumori multipli del sistema nervoso centrale (es., meningiomi, astrocitomi, ependimomi); (5) lesioni cutanee: (a) placche NF2 (schwannomi cutanei); (b) (poche) macchie caffellatte; (6) malformazioni dello sviluppo corticale cerebrale. La prevalenza della (forma sintomatica di) NF2 nella popolazione generale è di 1 su 100.000-200.000 individui con unincidenza di 1 su 33.000 nati. La forma classica a esordio nel giovane adulto è conosciuta come forma di Gardner, (esordio intorno ai 20-30 anni detà) con manifestazioni legate agli schwannomi bilaterali del nervo acustico/vestibolare (diminuzione/perdita progressiva delludito, tinnito, vertigini) e/o più raramente con manifestazioni da (altri) tumori del sistema nervoso centrale e/o periferico. In età pediatrica il fenotipo è diverso (forma di Wishart): per primi compaiono abitualmente i tumori del sistema nervoso centrale in assenza di schwannomi vestibolari; si possono avere macchie caffellatte e placche NF2 e solo dopo anni i tumori del nervo cranico VIII e di altri nervi cranici. Il quadro è più grave. Esiste anche una forma congenita ad esordio nei primi giorni/mesi di vita, con schwannomi vestibolari di piccole dimensioni (stabili nel tempo: anche per anni/decenni ma con improvvisa e rapida progressione) e numerose placche NF2; in questa forma le altre manifestazioni (es. meningiomi, altri tumori, altri schwannomi) sono spesso più gravi e progressive delle altre forme. Il gene responsabile della NF2 è localizzato sul cromosoma 22q12.1. Il prodotto genico della NF2 è conosciuto con il nome di schwannomina o merlina [dalla famiglia di proteine 4.1 del tipo moesina-ezrina-radixina/ERM alla quale appartiene il gene della NF2) e ha funzioni di regolazione della crescita e del rimodellamento cellulare (soppressione della crescita cellulare e della tumorigenesi)]. Alcune persone possono presentare tutte le (o parte delle) manifestazioni della NF2 in un emilato o in segmenti corporei circoscritti [NF2 a mosaico]. Altre persone presentano schwannomi (confermati istologicamente) dei nervi periferici (non intradermici) e/o delle radici gangliari in assenza di tumori del nervo vestibolare (o di altri nervi cranici: anche se in alcuni casi vi possono essere anche tumori unilaterali o bilaterali del nervo acustico/vestibolare e/o dei nervi cranici misti) o di altri segni diagnostici per la NF2 [Schwannomatosi, SWNTS]. Lesordio in questa forma è intorno ai 30 anni detà (sono conosciuti casi in età pediatrica) con tumori in svariate sedi (abitualmente tronco e arti). Si conoscono due forme principali: (1) SWNTS1 [MIM # 162091] causata da alterazioni del gene SMARCB1 [regolatore della cromatina actina-dipendente associato alla matrice e correlato alle proteina SWI/SBF, sub-famiglia B, membro di tipo 1; MIM # 601607], sul cromosoma 22q11.23 (posizione centromerica rispetto al gene della NF2); (2) SWNTS2 [MIM # 615670] causata da alterazioni del gene LZTR1 [regolatore della trascrizione di tipo 1 legato alla Leucina; MIM # 600574], cromosoma 22q11.21 (posizione centromerica rispetto al gene SMARCB1) che codifica per una proteina, membro della super-famiglia BTB-kelch. Il meccanismo molecolare della Schwannomatosi comprende: (1) mutazione germinale del gene SMARCB1 o del gene LZTR1; (2) ampia delezione allinterno del cromosoma 22 (con perdita del gene NF2 e dellallele intatto SMARCB1 o LZTR1); e (3) mutazione somatica dellallele intatto del gene NF2 [meccanismo conosciuto come four hits: Quadrupla alterazione (su entrambi gli alleli dei due geni SWNTS/NF2), con tre passaggi consecutivi]. Negli ultimi anni, accanto alle tradizionali terapie chirurgiche e/o radioterapiche sono stati anche impiegati diversi farmaci biologici (es., Lapatinib e Bevacizumab) con effetti di riduzione/arresto della crescita dei tipici tumori NF2.

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Herrero San Martín, A., and A. Alcalá-Galiano. "Schwannoma del nervio tibial en un paciente con schwannomatosis asociada a una nueva mutación en el gen LZTR1." Neurología 35, no. 9 (November 2020): 657–59. http://dx.doi.org/10.1016/j.nrl.2019.07.003.

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45

Журкова, Н. В., Л. А. Гандаева, А. А. Пушков, Е. Н. Басаргина, А. В. Пахомов, С. К. Труфанов, А. Ю. Алексеева, and К. В. Савостьянов. "RASopathies in multidisciplinary pediatric hospita." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 8(217) (August 31, 2020): 21–23. http://dx.doi.org/10.25557/2073-7998.2020.08.21-23.

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RAS-патии - группа наследственных заболеваний, возникающая вследствие нарушения регуляции функции RAS/MAPK внутриклеточных путей (Ras/mitogen-activated protein kinase). Суммарная частота заболеваний данной группы - 1 случай на 1000 новорожденных. Наиболее часто среди RAS-патий встречается синдром Нунан. В настоящее время описано 13 генов, мутации которых отвечают за развитие данного заболевания, включая ген SHOC2, ассоциированный с Нунан-подобным синдромом и измененной структурой волос (Noonan-like syndrome with loose anagen hair) и ген LZTR1, мутации в котором приводят к развитию синдрома Нунан, тип 2 с аутосомно-рецессивным типом наследования. RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

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Magro, Gaetano, Giuseppe Broggi, Giuseppe Angelico, Lidia Puzzo, Giada Maria Vecchio, Valentina Virzì, Lucia Salvatorelli, and Martino Ruggieri. "Practical Approach to Histological Diagnosis of Peripheral Nerve Sheath Tumors: An Update." Diagnostics 12, no. 6 (June 14, 2022): 1463. http://dx.doi.org/10.3390/diagnostics12061463.

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Peripheral nerve sheath tumors encompass a wide spectrum of lesions with different biological behavior, including both benign and malignant neoplasms as well as the recent diagnostic category, i.e., “atypical neurofibromatous neoplasm with uncertain biologic potential” to be used only for NF1 patients. Neurofibromas and schwannomas are benign Schwann-cell-derived peripheral nerve sheath tumors arising as isolated lesions or within the context of classical neurofibromatosis or schwannomatoses. Multiple tumors are a hallmark of neurofibromatosis type 1(NF1) and related forms, NF2-related-schwannomatosis (formerly NF2) or SMARCB1/LZTR1-related schwannomatoses. Perineuriomas are benign, mostly sporadic, peripheral nerve sheath tumors that show morphological, immunohistochemical, and ultrastructural features reminiscent of perineurial differentiation. Hybrid tumors exist, with the most common lesions represented by a variable mixture of neurofibromas, schwannomas, and perineuriomas. Conversely, malignant peripheral nerve sheath tumors are soft tissue sarcomas that may arise from a peripheral nerve or a pre-existing neurofibroma, and in about 50% of cases, these tumors are associated with NF1. The present review emphasizes the main clinicopathologic features of each pathological entity, focusing on the diagnostic clues and unusual morphological variants.

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47

Herrero San Martín, A., and A. Alcalá-Galiano. "Schwannoma of the posterior tibial nerve in a patient with schwannomatosis and a novel mutation of the LZTR1 gene." Neurología (English Edition) 35, no. 9 (November 2020): 657–59. http://dx.doi.org/10.1016/j.nrleng.2019.07.005.

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Motta, Marialetizia, Miray Fidan, Emanuele Bellacchio, Francesca Pantaleoni, Konstantin Schneider-Heieck, Simona Coppola, Guntram Borck, et al. "Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling." Human Molecular Genetics 28, no. 6 (November 27, 2018): 1007–22. http://dx.doi.org/10.1093/hmg/ddy412.

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Hutter, Sonja, Rosario M. Piro, David E. Reuss, Volker Hovestadt, Felix Sahm, Said Farschtschi, Hildegard Kehrer-Sawatzki, et al. "Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants." Acta Neuropathologica 128, no. 3 (July 10, 2014): 449–52. http://dx.doi.org/10.1007/s00401-014-1311-1.

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50

Janas-Naze, Anna, Konrad Malkiewicz, and Wei Zhang. "Clinical Findings in Children with Noonan Syndrome—A 17-Year Retrospective Study in an Oral Surgery Center." Children 9, no. 10 (September 28, 2022): 1486. http://dx.doi.org/10.3390/children9101486.

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To date, only a limited number of publications have studied the specific oral and maxillofacial findings in patients diagnosed with Noonan syndrome (NS), which is an example of a genetically heterogeneous RASopathy. In this retrospective study, we aimed to ascertain the genotype–phenotype correlations between genetic mutations and certain diagnoses in the field of oral surgery. We collected surgical and genetic data from 42 children (median age, 12 years) who had a confirmed diagnosis of NS and underwent surgery in the Department of Oral Surgery, Medical University of Lodz, over a 17-year period, from 2004 to 2021. In total, 17 patients with mutations of the PTPN11 gene were diagnosed with over-retained deciduous teeth and supernumerary teeth. An amount of 7 patients with mutations of the SOS1 gene were diagnosed with mandibular compound odontomas. Finally, 12 patients with mutations of the LZTR1 gene were diagnosed with bilateral or unilateral central giant cell granulomas in the mandible. Although craniofacial features of many genetic disorders have been previously described in the literature, this study determined the genotype–phenotype correlations in the field of oral surgery.

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