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: 10.99). 12/1999; 65(5):1342-8. DOI: 10.1086/302639
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Pascale Schneider, Aug 13, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer genome analyses have revealed that the enzymes involved in epigenetic gene regulation are frequently deregulated in cancer. Here we describe the enzymes that control the epigenetic state of the cell, how they are affected in cancer and how this knowledge can be exploited to treat cancer with a new arsenal of selective therapies.
    Oncogene 12/2011; 31(34):3827-44. DOI:10.1038/onc.2011.552 · 8.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.
    Revue Neurologique 05/2011; 167(5):431-48. · 0.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Molecular biology of the cell 06/2009; 20(14):3192-9. DOI:10.1091/mbc.E08-12-1224 · 5.98 Impact Factor