How does a retinoblastoma (RB) gene defect lead to retinoblastoma and osteosarcoma?

From the Guidelines

The RB gene defect leads to retinoblastoma and osteosarcoma through loss of tumor suppressor function, resulting in uncontrolled cell division and tumor formation in susceptible tissues. The RB gene normally produces the retinoblastoma protein (pRB), which regulates cell division by controlling progression through the cell cycle, particularly at the G1 checkpoint 1. When both copies of the RB gene are inactivated (through inherited mutation in one copy and somatic mutation in the second copy, or through two somatic mutations), cells lose this critical growth regulation. In retinoblastoma, this occurs in developing retinal cells, allowing uncontrolled proliferation of immature retinal cells. In osteosarcoma, the same mechanism affects bone-forming cells, particularly during periods of rapid bone growth such as adolescence, as noted in recent guidelines for bone cancer management 1.

This explains why osteosarcoma often develops in teenagers and why patients with hereditary retinoblastoma have a higher risk of developing osteosarcoma later in life. The RB protein normally binds to and inhibits E2F transcription factors, preventing the expression of genes required for DNA replication. Without functional pRB, E2F remains active, driving continuous cell division and eventually leading to tumor formation in susceptible tissues. Key points to consider include:

• The increased risk of osteosarcoma in patients with hereditary retinoblastoma due to the RB gene defect 1
• The importance of long-term follow-up for adult survivors of heritable retinoblastoma to monitor for secondary malignancies, including osteosarcoma 1
• The role of the RB gene in regulating cell division and preventing tumor formation, and the consequences of its inactivation 1

From the Research

Mechanism of rb Gene Defect

• The retinoblastoma (RB) gene is a tumor-suppressor gene that plays a crucial role in controlling cell proliferation and differentiation 2, 3.
• Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma that arise in families that carry mutant RB 2, 3.
• The RB protein acts as a cell cycle control checkpoint at the G1 phase, and its inactivation can lead to uncontrolled cell growth and tumor formation 3.

Role of RB Gene in Retinoblastoma and Osteosarcoma

• Retinoblastoma is a childhood malignant intraocular tumor that can be caused by mutations in the RB gene 4.
• Osteosarcoma is a type of bone cancer that can also be caused by mutations in the RB gene, particularly in families with a history of retinoblastoma 2, 3.
• The RB gene defect can lead to the development of retinoblastoma and osteosarcoma by disrupting normal cell cycle control and allowing for uncontrolled cell growth and tumor formation 2, 3.

Interaction with Other Proteins

• The RB protein can interact with other cellular proteins, including the transcription factor E2F, to regulate cell cycle control and differentiation 3.
• Transforming proteins encoded by certain viruses, such as SV40 and adenoviruses, can bind to the RB protein and block its normal function, leading to tumor formation 3.

Consequences of RB Gene Defect

• The RB gene defect can lead to a range of consequences, including retinoblastoma, osteosarcoma, and other types of cancer 2, 3.
• The defect can also lead to disturbed neural and hematopoietic differentiation, as seen in RB gene knock-out mice 3.
• Treatment options for retinoblastoma and osteosarcoma include chemotherapy, radiation therapy, and surgery, although the optimal treatment approach is still being researched 5, 4, 6.