The integrated landscape of driver genomic alterations in glioblastoma

Frattini, Véronique; Трифонов, Владимир; Chan, Joseph M.; Castano, Angelica; Lia, Marie; Abate, Francesco; Keir, Stephen T.; Ji, Alan X.; Zoppoli, Pietro; Niola, Francesco; Danussi, Carla; Dolgalev, Igor; Porrati, Paola; Pellegatta, Serena; Heguy, Adriana; Gupta, Gaurav; Pisapia, David; Canoll, Peter; Bruce, Jeffrey N.; McLendon, Roger E.; Yan, Hai; Aldape, Kenneth; Finocchiaro, Gaetano; Mikkelsen, Tom; Privé, Gilbert G.; Bigner, Darell D.; Lasorella, Anna; Rabadán, Raúl; Iavarone, Antonio

doi:10.1038/ng.2734

Cited by 467 publications

(465 citation statements)

References 64 publications

(47 reference statements)

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“…We found 24 patients, from 22 unrelated families, carrying germline variants of LZTR1. Unlike glioblastomas, where somatic variants are preferentially located in the Kelch domains of the LZTR1 protein, 24 our data confirm that, in schwannomatosis patients, germline LZTR1 variants occur along the entire sequence of the gene. However, we identified LZTR1 variants in a lower proportion of patients compared with the earlier report: 10 43% versus 100% and 30% versus 73% of familial and sporadic patients, respectively.…”

Section: Discussionsupporting

confidence: 71%

“…27 Recent studies also suggest that LZTR1 is an adaptor in CUL3 ubiquitin ligase complexes. 24 The tumor suppressor SMARCB1 is a core component of the SWI/SNF chromatin remodeling complex; 28 the complex is involved in nucleosome mobilization and makes compacted DNA accessible to transcription factors and repair enzymes. In the future, schwannomatosis research will be focused on understanding how proteins with so dissimilar functions could cause the same disorder.…”

Section: Discussionmentioning

confidence: 99%

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Expanding the mutational spectrum of LZTR1 in schwannomatosis

et al. 2014

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Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Expanding the mutational spectrum of LZTR1 in schwannomatosis

et al. 2014

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“…5,8,20,23 The median survival of glioblastoma patients is still only around 14 months, despite improvements in the standard of care, including resection, radiotherapy, and chemotherapy. This dismal clinical outcome makes glioblastoma an urgent subject of cancer research.…”

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confidence: 99%

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

Jiang

Yan

et al. 2016

JNS

149

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M alignant gliomas are the most common type of primary malignant brain tumor, and more than half of all gliomas are glioblastomas (Grade IV astrocytoma), one of the most aggressive and lethal types of brain tumor. Glioblastoma cells easily infiltrate into the normal cerebral cortex, ultimately resulting in the death of the patient. Well-defined risk factors for glioblastoma include radiation exposure and certain genetic syndromes. 21Several molecular and genomic datasets have recently been generated that have allowed identification of at least 4 subtypes of glioblastoma: classical, mesenchymal, proneural, and neural.14 Previous studies in glioblastoma geabbreviatioNs FBS = fetal bovine serum; HCC = hepatocellular carcinoma; HUVEC = human umbilical vein endothelial cell; lncRNA = long noncoding RNA; ncRNA = noncoding RNA; RT-qPCR = real-time quantitative reverse transcription polymerase chain reaction; SD = standard deviation. 3 Department of Respiratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing; and 4 Department of Oncology, The Second Affiliated Hospital of Suzhou University, Suzhou, China obJective Increased levels of H19 long noncoding RNA (lncRNA) have been observed in many cancers, suggesting that overexpression of H19 may be important in the development of carcinogenesis. However, the role of H19 in human glioblastoma is still unclear. The object of this study was to examine the level of H19 in glioblastoma samples and investigate the role of H19 in glioblastoma carcinogenesis. methods Glioblastoma and nontumor brain tissue specimens were obtained from tissue obtained during tumor resection in 30 patients with glioblastoma. The level of H19 lncRNA was detected by real-time quantitative reverse transcription polymerase chain reaction. The role of H19 in invasion, angiogenesis, and stemness of glioblastoma cells was then investigated using commercially produced cell lines (U87 and U373). The effects of H19 overexpression on glioblastoma cell invasion and angiogenesis were detected by in vitro Matrigel invasion and endothelial tube formation assay. The effects of H19 on glioblastoma cell stemness and tumorigenicity were investigated by neurosphere formation and an in vivo murine xenograft model. results The authors found that H19 is significantly overexpressed in glioblastoma tissues, and the level of expression was associated with patient survival. In the subsequent investigations, the authors found that overexpression of H19 promotes glioblastoma cell invasion and angiogenesis in vitro. Interestingly, H19 was also significantly overexpressed in CD133 + glioblastoma cells, and overexpression of H19 was associated with increased neurosphere formation of glioblastoma cells. Finally, stable overexpression of H19 was associated with increased tumor growth in the murine xenograft model. coNclusioNs The results of this study suggest that increased expression of H19 lncRNA promotes invasion, angiogenesis, stemness, and tumorigenicity of glioblastoma cells. Taken together, the...

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“…The implication of LZTR1 in human disease was first reported with the DiGeorge Syndrome, as it was deleted in the majority of DiGeorge Syndrome patients [13]. More recently, somatic mutations with loss of heterozygosity in LZTR1 and germline loss-of-function variants in LZTR1 were respectively associated with glioblastoma multiforme [14] and schwannomatosis [15,16].…”

Section: Discussionmentioning

confidence: 99%