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

Centre Hospitalier Universitaire Rouen, Rouen, Haute-Normandie, France
The American Journal of Human Genetics (Impact Factor: 10.93). 12/1999; 65(5):1342-8. DOI: 10.1086/302639
Source: PubMed


Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been documented in malignant rhabdoid tumor (MRT), one of the most aggressive human cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now report the presence of loss-of-function mutations of this gene in the constitutional DNA from affected members but not from healthy relatives in cancer-prone families. Furthermore, a constitutional mutation is documented in a patient with two successive primary cancers. In agreement with the two-hit model, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutation carriers. In all tested cases, DNA from parents demonstrated normal hSNF5/INI1 sequences, therefore indicating the de novo occurrence of the mutation, which was shown to involve the maternal allele in one case and the paternal allele in two other cases. These data indicate that constitutional mutation of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor. This condition, which we propose to term "rhabdoid predisposition syndrome," may account for previous observations of familial and multifocal cases of the aforementioned tumor types. It could also provide the molecular basis for cases of Li-Fraumeni syndrome without p53 germline mutations.

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Available from: Pascale Schneider, Aug 13, 2014
    • "Efforts to identify more effective treatments of CPC have been hindered by poor understanding of its pathogenesis. Germline deletion of hSNF5/INI1 or mutation of TP53 predisposes to CPC in humans (Garber et al., 1991; Malkin et al., 1990; Olivier et al., 2003; Sevenet et al., 1999; Tinat et al., 2009) and ablation of Tp53 and/or Rb function causes CPCs in mice (Brinster et al., 1984; Sáenz Robles et al., 1994). Deletion of PTEN has also been implicated in CPC, but activated oncogenes have not been described (Morigaki et al., 2012; Rickert et al., 2002; Ruland et al., 2014). "
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    ABSTRACT: Choroid plexus carcinomas (CPCs) are poorly understood and frequently lethal brain tumors with few treatment options. Using a mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for oncogenes within syntenic regions of chromosome gain. TAF12, NFYC, and RAD54L co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 were identified as oncogenes that are gained in tumors in both species and required for disease initiation and progression. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair. Our data identify a group of concurrently gained oncogenes that cooperate in the formation of CPC and reveal potential avenues for therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · Cancer cell
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    • "BAF47/INI1 plays a crucial role in orchestrating the balance between pluripotency and cell differentiation in embryonic stem cells [14]. Moreover, BAF47/INI1 is a tumor suppressor gene [15], since constitutive mutations have been associated with a strong predisposition to develop malignant rhabdoïd tumors, some of which could be of myogenic origin [16], [17], [18]. One consequence of BAF47/INI1 loss is the activation of gene expression programs that are associated with proliferation [19], [20], [21], [22]. "
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    ABSTRACT: Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes.
    Full-text · Article · Oct 2014 · PLoS ONE
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    • "Uniprot does not annotate a functional domain for these amino acids, indicating that variants in the other exons might yet be pathogenic. Like SMARCA4, haploinsufficiency of SMARCB1 causes rhabdoid tumor predisposition syndrome [Sevenet et al., 1999]. In addition, haploinsufficiency of SMARCB1 causes schwannomatosis in some families [Swensen et al., 2009]. "
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    ABSTRACT: De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype–phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.
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