Nearly all retinoblastoma is caused by errors (mutations) in both copies of the RB1 gene in a single retinal cell. The mutation may occur only in the cell that forms the cancer, or it may be present in cells throughout the body.
Most mutations can be found by molecular genetic testing of tumour or blood from the affected person.
A small number of children have two normal copies of RB1 and develop cancer due to changes on the MYCN gene.
Heritable RB1-/- Retinoblastoma
One copy of the RB1 gene is damaged in all, or nearly all cells of the body. This is because the mutation was inherited from a parent, or happened very soon after conception. This is called a constitutional mutation.
Children with a constitutional RB1 mutation usually develop multiple tumours in both eyes, A small number of children have one or more tumours in only one eye.
Sometimes, a benign “retinoma” is present in the eyes of blood relatives, indicating they carry a constitutional RB1 mutation. This is why the eyes of parents are examined at diagnosis of the child’s cancer.
Non-Heritable RB1-/- Retinoblastoma
The child inherits one normal copy of RB1 from each parent. Retinoblastoma occurs when both copies of the gene become damaged in a single retinal cell. All of these children develop only one tumour in one eye.
About 15% of children with unilateral retinoblastoma have a constitutional RB1 mutation. However, when there is no family history of retinoblastoma, precise molecular genetic testing is the only way to determine if the child’s retinoblastoma is heritable or non-heritable.
Non-Heritable RB1+/+MYCNA 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 (“Mick-En”), 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 with diagnosed 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.
When the RB1 gene mutation is known for the person who has retinoblastoma, genetic testing of blood relatives can determine risk to other children in the family. When genetic testing of a relative is negative, the individual does not carry the mutation, is not at risk and does not require further eye exams.
If the RB1 mutation in tumour or blood of the affected child is not known, infant blood relatives should be closely followed with regular eye exams up-to age five, so that if tumours form, they are discovered and treated as early as possible.
Sensitive molecular genetic testing can identify the RB1 gene mutation that caused retinoblastoma in 96% of families. However, this is a complex task, requiring expertise and technology available in only a few specialized laboratories focusing on retinoblastoma.
Molecular genetic testing is expensive and remains inaccessible to most families in the world.