hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors.
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The chromatin-remodeling hSNF5/INI1 gene has recently been shown to act as a tumor suppressor gene in rhabdoid tumors (RTs). In an attempt to further characterize the main chromosomal mechanisms involved in hSNF5/INI1 inactivation in RTs, we report here the molecular cytogenetic data obtained in 12 cell lines harboring hSNF5/INI1 mutations and/or deletions in relation to the molecular genetic analysis using polymorphic markers extended to both extremities of chromosome 22q. On the whole, mitotic recombination occurring in the proximal part of chromosome 22q, as demonstrated in five cases, and nondisjunction/duplication, highly suspected in two cases (processes leading respectively to partial or complete isodisomy), appear to be major mechanisms associated with hSNF5/INI1 inactivation. Such isodisomy accompanies each of the RTs exhibiting two cytogenetically normal chromosomes 22. This results in homozygosity for the mutation at the hSNF5/INI1 locus. An alternate mechanism accounting for hSNF5/INI1 inactivation observed in these tumors is homozygous deletion in the rhabdoid consensus region. This was observed in each of the four tumors carrying a chromosome 22q abnormality and, in particular, in the three tumors with chromosomal translocations. Only one case of our series illustrates the mutation/deletion classical model proposed for the double-hit inactivation of a tumor suppressor gene. (+info)
Clinicopathological characteristics of atypical teratoid/rhabdoid tumor.
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The clinicopathological features of atypical teratoid/rhabdoid tumor, a new entity among malignant pediatric brain tumors, and the differential diagnosis from primitive neuroectodermal tumor (PNET)/medulloblastoma, and germ cell tumor are described. Histologically, atypical teratoid/rhabdoid tumor is defined as a polymorphous neoplasm often featuring rhabdoid, PNET, epithelial, and mesenchymal components. Atypical teratoid/rhabdoid tumors usually include PNET components and occur mainly in the posterior fossa, so mimic medulloblastoma. Atypical teratoid/rhabdoid tumor is characterized by the cytogenetic finding of monosomy 22 rather than i(17q). The tumor is similarly mistaken for PNET at supratentorial sites. Germ cell tumors also enter into the differential diagnosis due to their histological immunophenotypic diversity, particularly features indicative of epithelial and mesenchymal differentiation. Nonetheless, the remarkable spectrum of tissues that typify teratoma is absent in atypical teratoid/rhabdoid tumor. The same is true of germ cell marker in tumor tissues and serum. The prognosis of atypical teratoid/rhabdoid tumor is far less favorable than that of PNET/medulloblastoma of malignant or germ cell tumor. Meta-analysis of 133 cases, including 15 new and 118 reported cases, confirm that atypical teratoid/rhabdoid tumor is as a clinicopathological entity and emphasizes the necessity for distinguishing this unique tumor from other pediatric central nervous system neoplasms. (+info)
Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers.
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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. (+info)
Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations.
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The hSNF5/INI1 gene which encodes a member of the SWI/SNF chromatin ATP-dependent remodeling complex, is a new tumor suppressor gene localized on chromosome 22q11.2 and recently shown to be mutated in malignant rhabdoid tumors. We have searched for hSNF5/INI1 mutations in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography. A total of 31 homozygous deletions and 36 point alterations were identified. Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and one editing mutations. Mutations were retrieved in most rhabdoid tumors, whatever their sites of occurrence, indicating the common pathogenetic origin of these tumors. Recurrent hSNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas. In contrast, hSNF5/INI1 point mutations were not detected in breast cancers, Wilms' tumors, gliomas, ependymomas, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.2 loci. These results suggest that rhabdoid tumors, choroid plexus carcinomas and a subset of medulloblastomas and cPNETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype. (+info)
Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors.
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The organization of genomic DNA into chromatin aids in the regulation of gene expression by limiting the access of transcriptional binding domains. The SWI/SNF family of chromatin-remodeling complexes, which are conserved from yeast to humans, open the chromatin to facilitate the transcriptional machinery to access their targets. The gene encoding the BAF47/hSNF5 subunit of the complex has been found mutated in both rhabdoid cell lines and in primary rhabdoid tumors. Since the pediatric tumors rhabdomyosarcoma (RMS) and Wilms' tumor (WT) share a similar genetic link with rhabdoid tumors, it was hypothesized that they may also show alterations of the BAF47 gene. Using primary tumors, the BAF47 protein was detected in all WT but less than 75% of the RMS tested. In cell lines, the BAF47 protein was missing in all rhabdoid cell lines and one RMS cell line. Analysis of sample DNA displayed either a mutation or deletion of the BAF47 gene in all samples negative for the protein. Several other subunits of the human SWI/SNF complex, including BRG1 which is the subunit directly interacting with the Rb tumor suppressor gene, were detected in all tumor samples. Alteration of BAF47 may be a genetic marker associated with the poor prognosis seen in all rhabdoid tumors but only some RMS. (+info)
Primary malignant rhabdoid tumours of brain, clinicoradiological findings of two cases.
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Malignant rhabdoid tumours (MRT) are extremely malignant, highly aggressive and uncommon renal neoplasms of childhood with very poor prognosis. About fifteen cases of primary intracranial MRT (with their clinical details) are reported in English literature, following the recognition of this entity in 1978. Two cases of MRT are reported here. The first case, one year male baby was admitted with a very large, infiltrative, posterior fossa mass. He required elective ventilation, following the tumour decompression but ultimately died of respiratory failure during the process of weaning from the ventilator. The second child was operated for an extremely vascular, very friable, solid and lobulated tumour of temporal lobe. Radical microsurgical decompression of mass was achieved, however the child developed massive recurrence, documented five weeks after the surgery while on radiotherapy. His recurrence showed partial response to radiotherapy and chemotherapy. The child is alive at 8 month's follow up, but probably passing the terminal days of his life. Hence the recognition of this entity is very essential for the aggressive management and prognostication of the patient, which obviously seems to be different from primitive neuroectodermal tumour. (+info)
Primary malignant rhabdoid tumor of the brain: CT and MR findings.
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PURPOSE: To describe the CT and MR findings of primary malignant rhabdoid tumor (MRT) of the brain, which is a rare but very aggressive neoplasm in childhood. MATERIALS AND METHODS: Retrospectively, we evaluated the CT and MR findings of 5 patients of primary MRT of the brain with a review of clinical records. RESULTS: The primary MRTs of the brain were large (n = 4) with a tendency to be associated with necrosis, hemorrhage (n = 2) and calcification (n = 2). Solid components of the tumor showed increased attenuation on precontrast CT scan and iso- or slightly hyper-signal intensity on T2-weighted images probably due to hypercellularity. Solid components of the tumor were also well enhanced on contrast-enhanced CT scan (n = 5) and MRI (n = 2). In 1 case with intratumoral bleeding, MR findings were variable on T1-weighted and T2-weighted images. Intracranial and intraspinal metastasis were found in 2 cases on preoperative MR studies. Follow-up CT and MR studies showed recurrence of the tumor and/or leptomeningeal metastasis in 3 cases. CONCLUSIONS: Although CT and MR findings of primary MRT of the brain are nonspecific, a tendency toward large size, calcification and intratumoral bleeding may be attributed to CT and MR findings. The solid components of tumors could present hyperdense on precontrast CT scan and iso- or slightly hyper-signal intensity on T2-weighted MR image. Preoperative and follow-up MR studies are important to detect metastatic foci. (+info)
Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.
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We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy. (+info)