SWI/SNF chromatin remodeling complexes and cancer

Abstract

The identification of mutations and deletions in the SMARCB1 locus in chromosome band 22q11.2 in pediatric rhabdoid tumors provided the first evidence for the involvement of the SWI/SNF chromatin remodeling complex in cancer. Over the last 15 years, alterations in more than 20 members of the complex have been reported in a variety of human tumors. These include germline mutations and copy number alterations in SMARCB1, SMARCA4, SMARCE1, and PBRM1 that predispose carriers to both benign and malignant neoplasms. Somatic mutations, structural abnormalities, or epigenetic modifications that lead to reduced or aberrant expression of complex members have now been reported in more than 20% of malignancies, including both solid tumors and hematologic disorders in both children and adults. In this review, we will highlight the role of SMARCB1 in cancer as a paradigm for other tumors with alterations in SWI/SNF complex members and demonstrate the broad spectrum of mutations observed in complex members in different tumor types.

Keywords: SMARCA4; SMARCB1; SWI/SNF; rhabdoid tumor.

Figure 1

BAF and PBAF complexes. The subunits specific to the BAF complex including ARID1A and ARID1B and to the PBAF complex including ARID2 and PBRM1 are demonstrated in the cartoon rendition of the complexes. Mutations in subunits colored in blue have been demonstrated in the literature to be associated with cancer, and subunits with mutations that have been associated with either cancer and/or known genetic disorders (i.e. Coffin-Siris syndrome) are colored in purple.

Figure 2

Germline SMARCB1 alterations in patients with rhabdoid tumor. Deletions of SMARCB1, both whole gene (22%) and intragenic (24%), encompass the majority of the germline alterations observed in rhabdoid tumors. A large percentage of the remaining germline alterations observed in SMARCB1 are frameshift mutations (20%) followed by nonsense mutations (17%). A smaller percentage of germline SMARCB1 alterations result from splice site mutations (10%) and partial gene duplications (7%).