SWI/SNF-Komplex-assoziierte Tumordispositions-Syndrome

Abstract

The SWI/SNF(SWItch/Sucrose Non-fermentable)-complexes are composed of several different subunits with specialized functions in specific tissues. These complexes are involved in chromatin re-modeling by regulating the ATP-dependent accessibility of transcription factors to functional elements within promoters and enhancers. Germline mutations in the genes SMARCB1, SMARCA4, SMARCE1 and PBRM1 encoding different SWI/SNF-complex subunits are associated with several hereditary cancer predisposition syndromes. For example, germline mutations in SMARCB1 and SMARCA4 may cause rhabdoid tumor predisposition syndromes RTPS1 and RTPS2, respectively. These syndromes are characterized by the occurrence of rhabdoid tumors of the brain (AT/RT), kidney (RTK) and soft tissues (MRT) in early infancy. In contrast to sporadic rhabdoid tumors, RTPS is characterized by the early onset of tumors (even prenatally), the development of multiple tumors and the presence of several affected family members. Sporadically occurring RT are characterized by somatic SMARCB1 or, less commonly observed, SMARCA4 mutations and are associated with a better prognosis than RTs occurring in patients with germline mutations of these genes. SMARCB1 and SMARCA4 may also predispose to other tumor types. Germline mutations in SMARCA4 have been identified in patients with small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), whereas SMARCB1 germline mutations may cause schwannomatosis, characterized by the development of benign nerve sheath tumors termed schwannomas. In contrast to RT and SCCOHT, schwannoma growth is not only dependent upon biallelic SMARCB1 mutations but also the inactivation of the NF2 gene. The heterogeneous spectrum of tumors caused by SMARCB1 inactivation is most likely associated with different types of germline mutation as well as the timing of the second hit mutations in the sense that the progenitor cells of rhabdoid tumors are only sensitive towards biallelic SMARCB1 loss during a brief developmental time-frame.