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

Laboratoire de Pathologie Moléculaire des Cancers, INSERM U 509, Institut Curie, Paris, 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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    • "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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    • "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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