Retinoblastoma Genetics Explained
All cancers are caused by genetic changes that influence division and growth of cells in our body.
Genes and Chromosomes
Genes are instructions controlling how we develop. They are packed together into 22 pairs of chromosomes, one set inherited from each parent. The x and y chromosomes (sex chromosomes) are unpaired.
Chromosomes are structures of DNA and protein that can be seen under a microscope. Genes can only be decoded using DNA analysis or molecular genetics.
Genes are copied during the constant process of cell division that causes us to grow. Mistakes can happen during that process.
Genes That Initiate Retinoblastoma
Retinoblastoma genetics are complex, involving a number of different genes. Below we focus on the two genes that spark eye cancer in children.
The RB1 gene is found on chromosome 13q. We all have two copies – one inherited from each parent. Benign retinoma forms when both copies of the gene in a single retinal cell are damaged. Subsequent mutations on other genes in the cell cause the retinoma to become malignant retinoblastoma, and influence how fast it grows.
The MYCN gene (pronounced “Mick-En”) is located on chromosome 2p. Retinoblastoma forms when a child acquires too many copies of this gene in a single retinal cell. Subsequent mutations on other genes in the cell determine how fast the cancer develops.
There are three groups of genetic retinoblastoma:
RB1-/- Heritable Retinoblastoma
The child either inherits one damaged copy of the RB1 gene from a parent, or one copy is damaged or lost very early in foetal development. This means all, or nearly all the cells in the body have one normal copy and one damaged copy of RB1. This is known as a constitutional RB1 mutation. When the mutation happens after conception, the child will have a mosaic mutation.
If the normal copy becomes damaged, a retinoblastoma will develop. This is why most children with heritable retinoblastoma develop multiple tumours in both eyes.
Over 90% of children with a constitutional RB1 mutation develop retinoblastoma. Most will develop a number of tumours in both eyes. Some have more than one tumour but only in one eye. A few develop one tumour in one eye. Rarely, a child will not develop retinoblastoma, because the normal copy of RB1 is not damaged in any retinal cell.
RB1-/- Non-Heritable Retinoblastoma
The child inherits one normal copy of the RB1 gene from each parent. Retinoblastoma occurs when both copies of the gene are damaged in a single retinal cell. These children develop only one tumour in one eye.
RB1+/+MYCNA Non-Heritable Retinoblastoma
About 1.4% of children with unilateral retinoblastoma and no family history have two normal copies of RB1. However, they have too many copies (amplification) of MYCN, a gene most commonly associated with neuroblastoma.
These children develop one tumour in one eye that is highly aggressive and becomes very dangerous at an early age. Risk for a baby diagnosed with unilateral cancer at 6 months old to have RB1+/+MYCNA retinoblastoma is 20%; the younger the baby, the more likely they are to have MYCN initiated retinoblastoma.
This type of retinoblastoma is not inherited and there is no risk to other family members or to children of the patient.
Who Has Heritable Retinoblastoma?
All children with bilateral or trilateral retinoblastoma, and about 17% of children with unilateral retinoblastoma have heritable retinoblastoma. Multifocal retinoblastoma indicates a constitutional RB1 mutation, but it is difficult to differentiate between true tumours and large seeds – fragments that have broken away from a single tumour.
When a child has unilateral retinoblastoma and no family history, precise molecular genetic testing is the only way to determine their risk for heritable retinoblastoma.
Implications of a Constitutional RB1 Mutation
Carriers of a constitutional RB1 mutation have a 50/50 chance of passing the damaged gene to their children, but only 10% of heritable retinoblastoma is actually inherited from a parent.
Carriers also have an increased risk of other tumours later in life. Second Primary Tumours usually affect the bones, soft tissue, muscles, skin or brain. Survivors of non-heritable retinoblastoma have the same cancer risk as the general population.