RB1

About RB1

RB1 on chromosome 13q14.2 was the first tumor suppressor gene to be cloned, in 1986, following the two hit hypothesis proposed in 1971 by Alfred Knudson from studies of retinoblastoma. It encodes the retinoblastoma protein, pRb, a key checkpoint at the G1 to S transition of the cell cycle. pRb binds and inhibits E2F transcription factors, preventing cells from entering S phase, and phosphorylation by cyclin D with CDK4 or CDK6 releases E2F and allows cell cycle progression. This pathway, involving CDKN2A, cyclin D, CDK4 and CDK6, RB1, and E2F, is disrupted in most human cancers. Germline RB1 variants cause hereditary retinoblastoma, an eye cancer of early childhood that is often bilateral and multifocal. Under the two hit model, the first hit is inherited and the second occurs somatically in a retinal cell, whereas sporadic unilateral retinoblastoma requires two somatic hits. Survivors of hereditary retinoblastoma have an increased risk of later cancers, especially osteosarcoma, soft tissue sarcomas, and melanoma. CDK4 and CDK6 inhibitors such as palbociclib, ribociclib, and abemaciclib, used in hormone receptor positive breast cancer, act on this pathway and require functional pRb.