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RB1
RB transcriptional corepressor 1
The RB1 gene provides instructions for producing the retinoblastoma protein (pRB), a crucial tumour suppressor that regulates cell growth and division, preventing uncontrolled proliferation. The RB1 gene plays a fundamental role in maintaining cellular integrity by controlling the cell cycle.
RB1 is located on the long (q) arm of chromosome 13, at band 13q14.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The RB1 gene, fully named RB transcriptional corepressor 1, is a vital component of the cellular machinery that controls cell proliferation and differentiation. It encodes the retinoblastoma protein (pRB), which functions as a tumour suppressor. This means pRB helps to prevent the formation and growth of tumours by regulating cell division, particularly by controlling when DNA replication occurs.
Disruptions to the normal function of the RB1 gene, often through pathogenic variants, can lead to uncontrolled cell division. This loss of cell cycle control is a hallmark of cancer development. The RB1 gene is particularly well-known for its association with retinoblastoma, a rare eye cancer predominantly affecting young children, but its involvement extends to a broader spectrum of other cancers.
What the gene does
The RB1 gene instructs cells to produce the pRB protein, a key negative regulator of the cell cycle. The primary role of pRB is to act as a tumour suppressor, ensuring that cells divide only when appropriate and under strict control. This regulation is critical for preventing the rapid and uncontrolled cell division characteristic of tumour growth.
pRB exerts its control by stopping other proteins from triggering DNA replication. Since DNA replication must occur before a cell can divide, tight regulation of this process controls cell division and helps prevent tumour growth.
Beyond cell cycle arrest, pRB also influences other crucial cellular processes, including cell survival, apoptosis (programmed cell death), and cellular differentiation. This multifaceted role underscores its importance in maintaining cellular homeostasis and preventing oncogenesis. When somatic variants occur in the RB1 gene, the pRB protein can become ineffective, leading to dysregulated cell division and tumour formation.
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Chromosome location
The RB1 gene is located on chromosome 13, specifically at position 13q14.2. This region is found on the long (q) arm of chromosome 13, within band 14, sub-band 2. The RB1 gene spans a significant portion of this chromosomal region. Understanding the precise genomic location of RB1 is crucial for genetic testing and diagnosing associated conditions. Patau syndrome, a chromosomal condition, is also linked to chromosome 13 [PMID:20301389].
Protein structure
The RB1 gene encodes a protein of 928 amino acids, known as the retinoblastoma protein (pRB). The structure of pRB is organised into several functional domains and regions that facilitate its diverse interactions and regulatory roles. At the N-terminus, there is a Disordered region spanning amino acids 1-42, which likely contributes to its flexibility and adaptability in binding.
A central and highly critical feature is the Pocket domain, located between amino acids 373-771. This region is fundamental for pRB's tumour suppressor function, as it is the primary site for binding to viral oncoproteins like T antigen and E1A, which are known to inactivate pRB. The Pocket domain itself is composed of two subdomains: Domain A (amino acids 373-579) and Domain B (amino acids 640-771), separated by a Spacer region (amino acids 580-639). Within this Spacer, there is another Disordered region from amino acids 610-632, suggesting conformational flexibility in this area.
Further towards the C-terminus, the Interaction with LIMD1 region (amino acids 763-928) and Domain C (amino acids 771-928) mediate additional protein-protein interactions, such as with E4F1. The very C-terminal end also contains a Disordered region (amino acids 860-928), which may play a role in regulatory phosphorylation events or partner recruitment. Importantly, a Bipartite nuclear localisation signal (amino acids 860-876) is situated within this C-terminal region, ensuring the correct nuclear targeting of pRB, where it performs its primary functions.
Key variants
Variants within the RB1 gene can significantly affect the production or function of the retinoblastoma protein (pRB). Pathogenic variants often lead to a non-functional or severely impaired protein, compromising its ability to regulate the cell cycle and suppress tumour growth. These variants can include missense changes, frameshift variants, nonsense variants, and large deletions, all of which can disrupt the gene's coding sequence.
The clinical consequences of RB1 variants primarily involve an increased susceptibility to various cancers. Given its classification under the ACMG SF v3.2 Secondary Findings list, detecting certain RB1 variants can have significant implications for an individual's health management, prompting further clinical evaluation and surveillance.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1024del | p.Thr342fs | Pathogenic | ★★☆☆ | Retinoblastoma |
c.1030C>T | p.Gln344Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.103C>T | p.Gln35Ter | Pathogenic | ★★☆☆ | Retinoblastoma |
c.1049+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinoblastoma |
c.1049+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinoblastoma |
c.1049+3A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinoblastoma |
c.1050-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinoblastoma |
c.1060_1061del | p.Gln354fs | Pathogenic | ★★☆☆ | Retinoblastoma |
c.1310del | p.Gly437fs | Pathogenic | ★★☆☆ | Retinoblastoma |
c.1421+1G>A | - | Pathogenic | ★★☆☆ | Retinoblastoma |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the RB1 gene are primarily associated with an increased risk of developing various cancers due to the loss of its critical tumour suppressor function. The most well-known condition linked to RB1 variants is hereditary Retinoblastoma, a type of eye cancer that typically affects young children. Hundreds of specific variants in the RB1 gene have been identified in individuals with retinoblastoma [PMID:31502476]. Individuals with germline RB1 variants are predisposed to this condition.
Beyond retinoblastoma, somatic (non-inherited) RB1 variants are implicated in the development and progression of several other cancers, including bladder cancer [PMID:31502476], cholangiocarcinoma, and lung cancer. Evidence also suggests associations with other malignancies such as breast cancer, melanoma, and a bone cancer known as osteosarcoma. These conditions highlight the broad impact of RB1 dysfunction across different tissue types.
Inheritance pattern
Conditions caused by pathogenic RB1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The RB1 gene is widely recognised in the UK clinical genomics landscape, featuring prominently in several NHS England Genomic Medicine Service (GMS) approved panels. It is listed as 'green' on PanelApp for its association with Adult solid tumours cancer susceptibility and Adult solid tumours for rare disease, indicating strong evidence for its involvement in these conditions.
Furthermore, RB1 is included in panels for Childhood solid tumours and Childhood solid tumours cancer susceptibility, reflecting its critical role in paediatric oncology. Specific panels such as Familial rhabdomyosarcoma, Retinoblastoma (R219), and Sarcoma of possible germline origin (R457) also classify RB1 as 'green', underscoring its established clinical utility in diagnosing and managing these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research into how specific lifestyle factors directly modify the effects of RB1 gene variants is ongoing and complex. However, general healthy lifestyle recommendations are relevant for individuals with an increased genetic predisposition to cancer, including those with RB1 variants. Maintaining a balanced diet rich in fruits, vegetables, and whole grains, and limiting processed foods and red meat, is generally advised for cancer prevention.
Engaging in regular physical activity can help maintain a healthy weight and has been associated with a reduced risk for several cancer types in the general population. Avoiding smoking and excessive alcohol consumption are also important, as these are well-established risk factors for many cancers. While these general health behaviours cannot alter an inherited genetic predisposition, they can contribute to overall well-being and potentially mitigate other environmental cancer risks.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat cancers associated with RB1 gene variants. The primary management for individuals with RB1-related conditions typically involves clinical surveillance and established medical interventions.
Individuals considering any dietary supplements should always consult with a healthcare professional. Some supplements may interact with medications or have unforeseen effects, particularly for those undergoing cancer treatment or management. A balanced diet generally provides sufficient nutrients, and supplements are not a substitute for a healthy lifestyle or medical care.
Frequently asked questions
What is the primary function of the RB1 gene?
The RB1 gene provides instructions for the pRB protein, a tumour suppressor. Its main role is to regulate the cell cycle, particularly preventing uncontrolled cell division, which is crucial for preventing tumour formation.
What conditions are associated with variants in the RB1 gene?
Variants in the RB1 gene are most notably associated with hereditary retinoblastoma, a rare eye cancer. They are also implicated in an increased risk of developing other cancers such as bladder cancer, lung cancer, and osteosarcoma [PMID:31502476].
Is retinoblastoma always inherited?
No, not all retinoblastomas are inherited. While germline (inherited) variants in the RB1 gene account for a significant portion, somatic (non-inherited) variants can also occur in retinal cells and lead to the development of retinoblastoma.
How does the pRB protein stop cells from dividing?
The pRB protein stops cells from dividing by preventing other proteins from triggering DNA replication. By controlling this process tightly, pRB can halt cell division when needed.
Are there any lifestyle changes that can prevent RB1-related cancers?
While lifestyle changes cannot alter an inherited genetic predisposition, maintaining a healthy lifestyle, including a balanced diet, regular physical activity, and avoiding smoking, can generally contribute to overall health and may reduce other environmental cancer risks.
What is the significance of RB1 being on the ACMG SF v3.2 Secondary Findings list?
Its inclusion on the ACMG SF v3.2 Secondary Findings list means that if pathogenic variants in RB1 are incidentally found during genetic testing for other reasons, these findings are considered clinically actionable and should be reported to the individual due to their significant health implications.
References
- Leiderman YI, Kiss S, Mukai S. Molecular genetics of RB1--the retinoblastoma gene. Seminars in ophthalmology. 2007. PMID: 18097988
- Sampieri K, Hadjistilianou T, Mari F. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations. Journal of human genetics. 2006. PMID: 16463005
- de Andrade AF, da Hora Barbosa R, Vargas FR. A molecular study of first and second RB1 mutational hits in retinoblastoma patients. Cancer genetics and cytogenetics. 2006. PMID: 16682285
- Knudsen ES, Knudsen KE. Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Experimental biology and medicine (Maywood, N.J.). 2006. PMID: 16816134
- Du W, Pogoriler J. Retinoblastoma family genes. Oncogene. 2006. PMID: 16936737
- Goodrich DW. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene. 2006. PMID: 16936742
- Wolff EM, Liang G, Jones PA. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nature clinical practice. Urology. 2005. PMID: 16474624
- Liu H, Dibling B, Spike B. New roles for the RB tumor suppressor protein. Current opinion in genetics & development. 2004. PMID: 15108806
- Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. American journal of medical genetics. Part C, Seminars in medical genetics. 2004. PMID: 15264269
- Richter S, Vandezande K, Chen N. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. American journal of human genetics. 2003. PMID: 12541220
- Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nature reviews. Cancer. 2002. PMID: 12459729
- Korabiowska M, Ruschenburg I, Betke H. Downregulation of the retinoblastoma gene expression in the progression of malignant melanoma. Pathobiology : journal of immunopathology, molecular and cellular biology. 2001. PMID: 12107345
- Herwig S, Strauss M. The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. European journal of biochemistry. 1997. PMID: 9219514