A deletion causing NF2 exon 9 skipping is associated with familial autosomal dominant intramedullary ependymoma

Zemmoura, Ilyess; Vourc’h, Patrick; Paubel, Agathe; Parfait, Béatrice; Cohen, Jérémy E.; Bilan, Frédéric; Kitzis, Alain; Rousselot, Cécilia; Parker, Fabrice; François, P.; Andres, Christian R.

doi:10.1093/neuonc/not165

Cited by 13 publications

(8 citation statements)

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“…The c.811-2A>T alteration is a splice-site mutation that at a minimum affects the FERM domain, important for Merlin’s localization and activation. In support of a functional role of this mutation, a 69bp deletion encompassing this exon 9 splice site and causing NF2 exon 9 skipping has been associated with familial autosomal dominant intramedullary ependymoma (Zemmoura et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

et al. 2014

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SUMMARY Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation TKIs develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. Addition of rapamycin reversed resistance in vivo. Analysis of afatinib+cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib+cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

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Section: Resultsmentioning

confidence: 99%

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

et al. 2014

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“…Spinal ependymoma is a rare tumor of adults that represents about 60 % of spinal cords tumors. Pathophysiology of this tumor is not known so far but there is a high incidence (33 %) of spinal low grade ependymoma in patients with type 2 neurofibromatosis [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Spinal ependymoma in a patient with Kabuki syndrome: a case report

et al. 2015

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BackgroundKabuki syndrome is a rare disorder characterized by the association of mental retardation and postnatal growth deficiency with distinctive facial appearance, skeletal anomalies, cardiac and renal malformation. Two causative genes have been identified in patients with Kabuki syndrome. Mutation of KMT2D (MLL2) was identified in 55–80 % of patients, while 9–14 % of KMT2D negative patients have mutation in KDM6A gene. So far, few tumors have been reported in patients with Kabuki syndrome. We describe the first case of a patient with spinal ependymoma and Kabuki syndrome.Case presentationA 23 years old girl followed at our Center for KMT2D mutated Kabuki syndrome since she was 4 years old presented with acute lumbar pain and intermittent tactile hyposthenia of the feet. Spine magnetic resonance revealed a lumbar endocanalar mass. She underwent surgical resection of the lesion and histologic examination showed a tanycytic ependymoma (WHO grade II).ConclusionKabuki syndrome is not considered a cancer predisposition syndrome. Nonetheless, a number of tumors have been reported in patients with Kabuki syndrome. Spinal ependymoma is a rare disease in the pediatric and young adult population. Whereas NF2 mutations are frequently associated to ependymoma such an association has never been described in Kabuki syndrome. To our knowledge this is the first case of ependymoma in a KMT2D mutated Kabuki syndrome patient. Despite KMT2D role in cancer has previously been described, no genetic data are available for previously reported Kabuki syndrome patients with tumors. Nonetheless, the association of two rare diseases raises the suspicion for a common determinant.

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“…Constitutional splice‐site variants in the NF2 gene have been reported by a number of studies (Baser et al, 2004; Bijlsma et al, 1994; Bourn et al, 1995; Dewan et al, 2017; Ellis et al, 2011; Evans et al, 1998, 2005; Faudoa et al, 2000; Hagel et al, 2002; Jacoby et al, 1994, 1996, 1999; Kluwe et al, 1996, 1998, 2000; Louvrier et al, 2018; MacCollin et al, 1994; Mautner et al, 1996, 2002; Mérel et al, 1995; Mohyuddin et al, 2002; Parry et al, 1996; Pemov et al, 2020; Rouleau et al, 1993; Ruttledge et al, 1996; Sadler et al, 2020; Sainio et al, 2000; Seong et al, 2010; Sestini et al, 2000; Wallace et al, 2004; Zemmoura et al, 2014). An interesting characteristic of these variants is that they seem to give rise to heterogeneous phenotypes and their position in the gene has been reported to correlate with severity of disease.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

2021

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Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non‐mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non‐NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non‐NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

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A deletion causing NF2 exon 9 skipping is associated with familial autosomal dominant intramedullary ependymoma

Cited by 13 publications

References 37 publications

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

Spinal ependymoma in a patient with Kabuki syndrome: a case report

Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

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