Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas

Smith, Miriam J.; O’Sullivan, James; Bhaskar, Sanjeev S.; Hadfield, Kristen D.; Poke, Gemma; Caird, John; Sharif, Saba; Eccles, Diana; FitzPatrick, David R.; Rawluk, Daniel; Plessis, Daniel du; Newman, William G.; Evans, D. Gareth

doi:10.1038/ng.2552

Cited by 210 publications

(161 citation statements)

References 32 publications

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“…15 The mutations led to a nonfunctional product, and the tumors exhibited loss of heterozygosity consistent with a tumor suppressor action for SMARCE1. Sequencing of SMARCE1 from circulating lymphocytes in our patient identified a germline mutation.…”

Section: Smith Et Al Identified 4 Individuals Withmentioning

confidence: 99%

“…Immunohistochemical analysis of paraffin-embedded tumor tissue was negative for SMARCE1 protein 16 relative to control slides. 15 …”

Section: Pathological and Genetic Analysismentioning

confidence: 99%

“…This was predicted to result in a frameshift mutation. 15 Sequencing of tumor DNA from formalin-fixed tissue specimens detected loss of heterozygosity, noted as a reduced peak height of the wild-type SMARCE1 allele in tumor DNA compared with lymphocyte DNA (Fig. 4).…”

Section: Pathological and Genetic Analysismentioning

confidence: 99%

“…Recently, heterozygous loss-of-function mutations in the SWI/SNF chromatin remodeling complex subunit SMARCE1 were found in 4 individuals with familial multiple spinal meningiomas. 15 None of these individuals had features of neurofibromatosis Type 2 (NF2), and resected meningiomas were all of the clear cell variant. Mutations in SMARCE1 and other SWI/SNF subunits have been implicated in a number of human tumors.…”

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confidence: 99%

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SMARCE1 mutations in pediatric clear cell meningioma: case report

Evans¹,

Hoff

Hickey

et al. 2015

PED

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Clear cell meningioma (CCM) is an uncommon variant of meningioma. The authors describe a case of a pediatric CCM localized to the lumbar spine. After resection, sequencing revealed an inactivating mutation in the SWI/SNF chromatin remodeling complex subunit SMARCE1, with loss of the second allele in the tumor. The authors present a literature review of this mutation that is associated with CCM and a family history of spine tumors.

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Section: Smith Et Al Identified 4 Individuals Withmentioning

confidence: 99%

“…Immunohistochemical analysis of paraffin-embedded tumor tissue was negative for SMARCE1 protein 16 relative to control slides. 15 …”

Section: Pathological and Genetic Analysismentioning

confidence: 99%

Section: Pathological and Genetic Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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SMARCE1 mutations in pediatric clear cell meningioma: case report

Evans¹,

Hoff

Hickey

et al. 2015

PED

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“…6 Mutations in SMARCE1, which is involved in the regulation of secondary DNA structure within chromosomes, have also been reported to be important in the formation of multiple spinal meningiomas. 105 The study by Smith and colleagues identified SMARCE1 mutations in a group of individuals with familial multiple spinal meningiomas without NF2 mutations. Furthermore, SMARCE1 is mutated in cranial meningioma and associated with the clear cell subtype, which is a WHO Grade II tumor that tends to metastasize more frequently than other subtypes.…”

Section: Meningiomasmentioning

confidence: 99%

The genetic basis of intradural spinal tumors and its impact on clinical treatment

Karsy

Guan

Sivakumar

et al. 2015

FOC

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Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed.

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Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults

et al. 2017

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IMPORTANCE Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome.OBJECTIVE To determine the frequency of the known heritable meningioma-or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. DESIGN, SETTING, AND PARTICIPANTSUsing the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU. MAIN OUTCOMES AND MEASURESThe type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma-and meningioma-predisposing syndromes.RESULTS In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation.CONCLUSIONS AND RELEVANCE A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young...

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Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas

Cited by 210 publications

References 32 publications

SMARCE1 mutations in pediatric clear cell meningioma: case report

SMARCE1 mutations in pediatric clear cell meningioma: case report

The genetic basis of intradural spinal tumors and its impact on clinical treatment

Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults

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