The advent of exome sequencing across a diverse range of human cancers has led to the realization that BAF complexes are one of the most significant tumor suppressors in humans, with a cumulative incidence of mutation of more than 20% of human cancers sequenced to date (Fig. 3). However, the pathogenesis of this much larger group of tumors is almost certainly different from that of MRTs. Most cancers bearing BAF subunit mutations are found in older age groups, as is cancer in general, and do not occur selectively in young children. In addition, many, if not most, of the cancers have a mutation in only one allele of the affected subunit, making them dominant tumor suppressors, rather than recessive tumor suppressors as in the case of MRTs. Thus, the mechanism underlying tumor suppression by BAF subunits must relate to a defect that demonstrates dosage sensitivity, providing a ripe foundation for the assessment of possible mechanisms. Mutations that produce neurologic disease are also genetically dominant, suggesting that a single fundamental process, albeit context-dependent, is at fault in both neurologic disease and cancer caused by heterozygous mutations in BAF subunits.
