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Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations
N Sévenet1, A Lellouch-Tubiana, D Schofield
1Laboratoire de Pathologie Moléculaire des Cancers, INSERM U509, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France.
Abstract:
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.
Insights
Mutations in the hSNF5/INI1 gene are common in rhabdoid tumors, choroid plexus carcinomas, and some central primitive neuroectodermal tumors. These alterations suggest a shared oncogenic pathway in these aggressive childhood cancers.
Area of Science:
- Oncology
- Cancer Genetics
- Molecular Biology
Background:
- The hSNF5/INI1 gene, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor located on chromosome 22q11.2.
- Mutations in hSNF5/INI1 have been previously identified in malignant rhabdoid tumors.
- Understanding the role of hSNF5/INI1 alterations in various cancers is crucial for elucidating oncogenesis.
Purpose of the Study:
- To investigate the frequency and spectrum of hSNF5/INI1 mutations across a diverse range of tumor types.
- To identify specific cancers that share common genetic alterations involving the hSNF5/INI1 gene.
- To explore the pathogenetic relationship between hSNF5/INI1 alterations and specific pediatric malignancies.
Main Methods:
- Screening of 229 tumors from various origins for hSNF5/INI1 mutations using denaturing high-performance liquid chromatography.
- Identification and characterization of homozygous deletions and point alterations, including nonsense, frameshift, splice site, and missense mutations.
- Analysis of mutation distribution across the coding sequence and correlation with tumor type and clinical presentation.
Main Results:
- A total of 31 homozygous deletions and 36 point alterations in hSNF5/INI1 were identified.
- Mutations were prevalent in rhabdoid tumors, choroid plexus carcinomas, and a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas.
- hSNF5/INI1 point mutations were notably absent in breast cancers, Wilms' tumors, gliomas, ependymomas, and sarcomas, despite loss of heterozygosity at 22q11.2 in some cases.
Conclusions:
- Rhabdoid tumors, choroid plexus carcinomas, and a subset of medulloblastomas/cPNETs share common oncogenic pathways driven by hSNF5/INI1 alterations.
- hSNF5/INI1 mutations define a genetically homogeneous group of highly aggressive cancers, predominantly affecting young children.
- The presence or absence of a rhabdoid phenotype does not always correlate with hSNF5/INI1 mutation status, highlighting complex genotype-phenotype relationships.