it genetically less visible. Again, many of the subunits most highly mutated in cancer and human neurologic disease are not required for in vitro chromatin remodeling. The extensive genomic observations described above have placed a set of three constraints on the fundamental mechanism underlying tumor suppression by BAF complexes. The first is that the mechanism is dosage-sensitive, giving rise to genetic dominance. Second, the fundamental mechanism cannot be detected in an in vitro chromatin remodeling assay. Third, whereas this fundamental tumor-suppressive mechanism might be general, it manifests itself in a highly tumor-specific and apparently tissue-specific manner. For example, the ATPase BRG is mutated in more than 90% of small cell ovarian cancers (66, 67) but in less than 5% of small cell lung cancers. Thus, heterozygous mutations in BRG (SMARCA4) cause small cell ovarian cancer, but likely just bear passenger mutations related to dysfunction of genome maintenance mechanisms in certain other tumors in which they are less prevalent. These biologic observations are critical for designing approaches to understand the fundamental mechanism(s) of tumor suppression.
