Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers

Sévenet, Nicolas; Sheridan, Eammon; Amram, Daniel; Schneider, Pascale; Handgretinger, Rupert; Delattre, Olivier

doi:10.1086/302639

Cited by 403 publications

(245 citation statements)

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“…These tumors may occur in various organs including kidney, central nervous system (atypical teratoid and rhabdoid tumors, ATRT), liver, skin and soft tissues. The constitutional mutation of hSNF5/ INI1 is associated with a strong predisposition to develop these tumors (Sevenet et al, 1999). Mouse models have confirmed this tumor suppressor role: whereas Snf5/Ini1 homozygous deletion is embryonic lethal, heterozygous mice develop tumors that closely resemble MRTs and that demonstrate loss of heterozygosity of the wild-type allele (Klochendler-Yeivin et al, 2000;Roberts et al, 2000;Guidi et al, 2001).…”

Section: Introductionmentioning

confidence: 89%

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

et al. 2007

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ATP-dependent SWI/SNF chromatin remodeling complexes regulate cell-cycle and play critical roles in a variety of differentiation pathways. The core subunit SNF5/INI1 is a tumor suppressor that is inactivated in a highly aggressive childhood cancer of unknown cellular origin, termed malignant rhabdoid tumor (MRT). The highly undifferentiated phenotype of this tumor suggests that the loss-of-function of hSNF5/INI1 impairs specific differentiation programs of the MRT parental cell. Based on the hypothesis that these programs might be reinitialized upon hSNF5/INI1 re-expression in MRTs, we show that some MRT cell lines can differentiate toward the adipogenic lineage. We further show that the knock down of the SNF5/INI1 subunit abrogates adipocyte differentiation of murine 3T3-L1 preadipocytes and of human mesenchymal stem cells. Finally, we provide evidence that hSNF5/INI1 cooperates with C/EBPb and PPARc2 transcriptional regulators to activate the expression of adipocyte-specific genes. These data indicate that not only the ATPase subunit of the SWI/SNF complex, but also SNF5/INI1 is required for adipocyte differentiation. They further show that MRT cell lines harbor an adipogenic differentiation potential and that the tumor suppressor role of the SNF5/INI1 subunit may rely on its ability to regulate the balance between cell proliferation and differentiation.

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Section: Introductionmentioning

confidence: 89%

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

et al. 2007

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“…Although we were unable to demonstrate that the recombination event directly affected the coding regions of NF2, we nevertheless conclude that both tumours must have a common origin. Several patients with a constitutional INI1 mutation and with two tumours at different sites have been reported (Sevenet et al, 1999b;Savla et al, 2000;Kusafuka et al, 2004;Biegel, 2006;Giunti et al, 2006;Meyers et al, 2006). It will be of interest to determine whether the tumours of these patients, like those of patient III-1, are primary tumours, share somatic changes in the genome, and originate from a common precursor cell as well.…”

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

confidence: 99%

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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“…Paradoxically, disruption of SWI/SNF function has alternatively been associated with tumorigenesis and lack of cellular/organismal viability. Specifically, loss or mutation of the SNF5/INI1 subunit is associated with rhabdoid tumorigenesis, and it has been convincingly demonstrated that the SNF5/INI1 gene acts as a tumor suppressor (Biegel et al, 1999;Sevenet et al, 1999;Roberts et al, 2002). Correspondingly, diminished expression or loss of Brg1, Brm, Baf57, Baf180, and several other chromatin-modifying genes has been observed in cancer cell lines and tumor specimens (Gregory and Shiekhattar, 2004).…”

Section: Introductionmentioning

confidence: 99%

SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

Bourgo

Siddiqui

Fox

et al. 2009

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Switch (SWI)/sucrose nonfermentable (SNF)is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity. INTRODUCTIONThe switch/sucrose nonfermentable (SWI/SNF) complex uses the energy of ATP hydrolysis to modulate nucleosome position and density across promoters and thus plays an important role in regulating gene expression. The SWI/SNF ATPase function is necessary for its chromatin remodeling activities (Laurent et al., 1993), and this function is manifested through one of two mutually exclusive subunits, brahma-related gene 1 (Brg1) or brahma (Brm). Although both Brg1 and Brm can function as the central ATPase in the SWI/SNF complex, each defines a discrete complex with unique biochemical activity. In addition, specific accessory factors interact with the ATPase subunits and play critical roles in chromatin remodeling activity. For example, SNF5/ BAF47/INI1 is present in both Brg1-and Brm-associated complexes and is required for maximal chromatin remodeling activity, both in vitro and in yeast. Surprisingly, although Brg1 and Brm have Ͼ75% sequence homology, the impact of each individual subunit on chromatin biology and underlying cell biology is poorly understood (Phelan et al., 1999).Due to its central function in chromatin remodeling, SWI/ SNF function is required in many facets of gene regulation. Correspondingly, it is estimated that approximately 5% of the yeast genome is transcriptionally regulated by the SWI/ SNF complex (Holstege et al., 1998;Sudarsanam et al., 2000). In mammalian cells, SWI/SNF plays a critical role in the activation of a diverse set of genes and has been shown to be recruited directly to transcriptional activation domains (De- Hassan et al., 2001). In contrast, SWI/ SNF is also required for transcriptional repression. For example, transcriptional repression of cell cycle genes mediated by the retinoblastoma tumor suppressor is dependent on SWI/SNF, implicating the involvement of SWI/SNF in cell...

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Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers

Cited by 403 publications

References 35 publications

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

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

SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity

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