Familial Posterior Fossa Brain Tumors of Infancy Secondary to Germline Mutation of the hSNF5 Gene

Taylor, Michael D.; Gökgöz, Nalan; Andrulis, Irene L.; Mainprize, Todd G.; Drake, James M.; Rutka, James T.

doi:10.1086/302833

Cited by 157 publications

(97 citation statements)

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“…This study thus documents the inheritance of a germline INI1-mutation that predisposes to the development of MBTs at young age in three subsequent generations of a family. Inheritance of an INI1-mutation via asymptomatic carriers has been reported before in two other families with childhood brain tumours (Taylor et al, 2000;Janson et al, 2006). Although the analyses of the latter families suggested that the asymptomatic transmission of the INI1-mutation exclusively occurred via female carriers, it is clear from our family that the transmission can as well take place via healthy male carriers.…”

Section: Discussion Inheritance Of the Ini1-mutationsupporting

confidence: 59%

“…Given the small number of splice site mutations in malignant rhabdoid tumours reported to date (Biegel, 2006), it is interesting to note that our family and one other multigeneration family with RTPS (Taylor et al, 2000) demonstrate an INI1 mutation at a splice site, raising the possibility that carriers of such a mutation may be less likely to be affected. In case of our family, there is the additional possibility that in the brain of the unaffected carriers alternative splicing of the INI1-mutant allele transcript, leading to absence of INI1 protein in the brain tumours of the patients, does not occur.…”

Section: Nf2 Rearrangement In the Tumours Of Patient Iii-1mentioning

confidence: 89%

“…Familial cases of AT/RT or CPC are very rare. Until now, two families have been described in which the development of these malignant childhood brain tumours correlated with the inheritance in two or more generations of a mutation in the INI1/hSNF5/BAF47/SMARCB1 gene on chromosome 22 (Taylor et al, 2000;Janson et al, 2006). This tumour suppressor gene encodes INI1, which is a core subunit of the chromatin remodelling SWI/SNF complex (Wang et al, 1996;Phelan et al, 1999).…”

mentioning

confidence: 99%

“…In one family, an 18-month-old girl presented with a cerebellar rhabdoid tumour with an INI1 exon 7 donorsplice site mutation, which she inherited from her unaffected carrier mother. A brother of the latter died at the age of 2 years of a tumour diagnosed as CPC with the same mutation (Taylor et al, 2000). In the other family, two half-brothers each developed an AT/RT at a young age and inherited an INI1 insertion mutation in exon 4 from their unaffected carrier mother.…”

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confidence: 99%

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Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

et al. 2007

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Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G4A mutation in the donor splice site of exon 4 (c.500 þ 1G4A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsensemediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

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Section: Discussion Inheritance Of the Ini1-mutationsupporting

confidence: 59%

Section: Nf2 Rearrangement In the Tumours Of Patient Iii-1mentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

et al. 2007

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“…SNF5 mutations are underlying familial cancers in which one SNF5 allele carries a germ-line mutation and the other allele is lost during tumorigenesis (Versteege et al 1998;Sevenet et al 1999;Taylor et al 2000). The tumor-suppressive effect of SNF5 is evident from the fact that reintroduction of SNF5 into SNF5-mutant tumor cells mediates cell cycle arrest (Betz et al 2002;Reincke et al 2003) and from mouse models demonstrating Snf5 as a haploinsufficient tumor-suppressor gene (Klochendler-Yeivin et al 2000;Roberts et al 2000), complete loss of which causes mice to succumb early in life to aggressive lymphomas or rhabdoid tumors (Roberts et al 2002).…”

Section: Messing Around With Nucleosomesmentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

442

318

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Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002). With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes. Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability. Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state. In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli. Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators. Understanding the molecular details behind "epigenetic cancer diseases" holds potentially important prospects for medical treatment, as it allows for novel strategies for drug development. A number of recent reviews have provided details on epigenetic mechanisms and their involvement in cancer, and we refer to these for more in-depth information on individual epigenetic mechanisms

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The Molecular Genetics of Schwannomatosis

Hulsebos

2009

Encyclopedia of Life Sciences

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Schwannomatosis is characterized by the development of multiple schwannomas, but without the involvement of vestibular schwannomas. Presence of the latter is the hallmark of neurofibromatosis type 2 (NF2). Recent studies in families with schwannomatosis have excluded the NF2 gene on chromosome 22 as the germline‐transmissible schwannomatosis gene. However, this gene was found to be somatically inactivated in schwannomas of the patients. In 2007, the INI1/SMARCB1 gene on chromosome 22 was identified as a strong candidate for the schwannomatosis‐predisposing gene. Subsequent studies have confirmed the involvement of this tumour suppressor gene in 40–50% of familial and about 10% of sporadic cases. INI1/SMARCB1 had earlier been found to be implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. It remains to be explained how INI1/SMARCB1 can be involved in the development of benign schwannomas and of malignant rhabdoid tumours as well. Key concepts Schwannomatosis is characterized by the development of multiple schwannomas but no vestibular schwannomas, which are diagnostic of neurofibromatosis type 2 (NF2). INI1/SMARCB1 on chromosome 22 is a schwannomatosis‐predisposing gene. Constitutional mutations in this gene are found in 40–50% of familial cases and about 10% of sporadic cases. INI1/SMARCB1 is a tumour suppressor gene of which the second wild‐type copy is found to be inactivated in the schwannomas of these patients. Inactivating mutations in the NF2 gene are also found in the schwannomas of schwannomatosis patients, but these are only somatically acquired. The INI1/SMARCB1 protein is a core subunit of the SWI/SNF complex. The SWI/SNF complex is involved in chromatin‐remodelling and in cancer development. INI1/SMARCB1 is also implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. Patients with rhabdoid tumour predisposition syndrome (RTPS) carry a constitutionally mutated INI1/SMARCB1 gene and may develop more than one rhabdoid tumour. It remains to be clarified how INI1/SMARCB1 can be involved in the development of two tumour types, schwannomas and rhabdoid tumours, with very different histologies and malignancy grades.

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Familial Posterior Fossa Brain Tumors of Infancy Secondary to Germline Mutation of the hSNF5 Gene

Cited by 157 publications

References 14 publications

Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

Epigenetics and cancer

The Molecular Genetics of Schwannomatosis

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