Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations

The hSNF5/INI1 gene which encodes a member of the SWI/SNF chromatin ATP-dep endent remodeling complex, is a new tumor suppressor gene localized on chro mosome 22q11.2 and recently shown to be mutated in malignant rhabdoid tumor s, We have searched for hSNF5/INI1 mutations in 229 tumors of various origi ns using a screening method based on denaturing high-performance liquid chr omatography, A total of 31 homozygous deletions and 36 point alterations we re identified, Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and o ne editing mutations. Mutations were retrieved in most rhabdoid tumors, wha tever their sites of occurrence, indicating the common pathogenetic origin of these tumors. Recurrent hSNF5/INI1 alterations were also observed in cho roid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas, In contrast, hSNF5/INI1 point mutati ons were not detected in breast cancers, Wilms' tumors, gliomas, ependymoma s, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.2 loci. These results suggest that rhabdoi d tumors, choroid plexus carcinomas and a subset of medulloblastomas and cP NETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of hi ghly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype.