RB1 gene and cancer
The RB1 gene, located on chromosome 13, is a critical tumor-suppressor gene that plays a vital role in regulating cell division. Its primary function is to produce the retinoblastoma protein (pRB), which controls the cell cycle by interacting with transcription factors and silencing specific genes. Inactivation of the RB1 gene can lead to retinoblastoma, a rare form of childhood cancer that typically manifests in children from in utero to around five years of age. There are two forms of retinoblastoma: hereditary, where one defective RB1 gene is inherited and the second copy is mutated during development, and sporadic, where both copies of the gene are mutated in the same somatic cell.
Retinoblastoma accounts for approximately 2-3% of cancers in children, with an incidence rate of about 1 in 14,000 to 1 in 20,000. Children with inherited RB1 mutations face an increased risk of developing other cancers later in life, such as those affecting the bladder, pineal gland, and skin. Molecular screening methods can help identify RB1 mutations, potentially reducing the need for invasive clinical screening. Understanding the RB1 gene's role in cancer helps in early detection and intervention strategies, which can significantly impact outcomes for affected individuals.
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RB1 gene and cancer
ALSO KNOWN AS: Retinoblastoma 1 (including osteosarcoma), OSRC
DEFINITION: The RB1 gene (a tumor-suppressor gene), which is 180 kilobase pairs with 27 exons, can become inactivated and cause retinoblastoma, a rare childhood cancer of the retina, occurring from in utero to about five years of age.
Gene location and function: The retinoblastoma gene, RB1, is on chromosome 13q14.2. This ubiquitously expressed gene codes for a 110 KDa tumor suppressor (pRB), which regulates cell division. The retinoblastoma protein regulates the progression of cells through the cell cycle and the exiting of differentiating cells from the cell cycle. This protein controls the cell cycle by sequestering transcription factors and by deacetylating histones, involved in gene silencing. Both copies of the RB1 gene must be mutated to lose the tumor-suppressor ability. Individuals with an inherited form of retinoblastoma have a germ-line mutation of one RB1 gene. During development, the second copy of the RB1 gene is mutated; control of the cell cycle is lost, and tumors develop. These tumors may be in both eyes. Other individuals have sporadic retinoblastoma in which mutations occur in the same somatic cell to inactivate both copies of the RB1 gene. Sporadic retinoblastoma is often in only one eye.
RB1 gene inactivation: Causes of RB1 gene inactivation include chromosome rearrangements of the 13q14 region, nucleotide changes, loss of heterozygosity (loss of the normal copy), and CpG hypermethylation in the RB1 promoter region (which silences the gene).
Molecular screening: Methods to screen for RB1 gene mutations include multiplex polymerase chain reaction (PCR) sequencing of the gene, a protein truncation test, and methylation analysis. The usual clinical screening for retinoblastoma requires examination of the eyes under anesthesia. Molecular screening could eliminate anesthesia-related risks and reduce the financial and psychological costs of clinical screening. Individuals without germ-line RB1 mutations will not need the clinical screening. Fetuses with highly penetrant germ-line mutations could be delivered early and treated sooner to save their vision. People with inherited forms of retinoblastoma (have one defective RB1 gene) have an increased risk of developing other cancers, such as those of the bladder, pineal gland, bone, and skin.
Incidence: Retinoblastoma accounts for between 2 and 3 percent of cancers in children under the age of fifteen. The frequency of retinoblastoma is between 1 in 14,000 and 1 in 20,000. About 60 percent of those with retinoblastoma have RB1 mutations only in the tumor and not in other cells. Some 40 percent of retinoblastoma cases are hereditary. Of hereditary cases, 90 percent are due to new mutations occurring near the time of conception; 10 percent are due to a mutation inherited from a parent. According to a study published in 2021 in the British Journal of Cancer, patients with hereditary retinoblastoma had a higher risk of developing other cancers, including sarcomas and melanoma, later in life. RB1 mutations also appeared to play a role in hastening the spread of advanced lung cancer to the bones.
Bibliography
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