Retinoblastoma is caused by errors in a gene called RB1. Each cell contains 2 copies of the RB1 gene that function to limit cell growth. As long as at least one of these RB1 genes functions normally, retinoblastoma will not develop. Retinoblastoma tumors develop in an immature retinal cell when neither copy of the tumor-suppressing RB1 gene is functioning. Several different kinds of DNA alterations in the RB1 gene can lead to retinoblastoma. Sometimes these changes in the RB1 gene can be found in body tissues outside of the eye, such as blood. All individuals with bilateral retinoblastoma have the hereditary form of retinoblastoma, and will have this RB1 gene change in their blood cells. Among individuals with unilateral retinoblastoma, it is estimated that 85% have the non-hereditary form of the disease in which the alterations in the RB1 gene are found only in the tumor. In the sporadic form of retinoblastoma, both copies of the RB1 gene are working normally in cells outside of the tumor. In the remaining 15% of unilateral cases, one copy of the RB1 gene is abnormal in other tissues of the body outside of the tumor. These individuals have the hereditary form of retinoblastoma.

Genetic Testing for the RB1 Gene

Genetic testing for the RB1 gene is currently available for individuals with bilateral or unilateral retinoblastoma. Testing is performed using DNA from a blood sample and DNA from a tumor sample (if available). In the past, a fresh frozen tumor sample was not always preserved, but now with genetic testing available, it is important that a frozen sample is kept for future DNA analysis.

In an individual with unilateral retinoblastoma, genetic testing is used to determine whether this individual has a sporadic form or hereditary form (germline mutation) of the disease. Currently genetic testing detects more than 90% of RB1 mutations. If RB1 DNA testing indicates that an individual is a carrier of an RB1 germline mutation, then testing for the parents, siblings, and future pregnancies (through amniocentesis or CVS) can be performed to determine more accurately the potential health and reproductive risks for this family. Individuals with the heritable form of retinoblastoma have a 50% chance of passing down the cancer predisposing RB1 mutation to their offspring.

If the result of an RB1 DNA test indicates that an individual has the non-hereditary form of retinoblastoma, then further testing for that individual's parents and siblings would not be necessary. However, DNA testing for the patient's offspring would be indicated because of the possibility of germline or gonadal mosaicism for an RB1 mutation that was not present or not detectable in the patient's blood cells.

Geneticic Counseling

Genetic counseling is important for families and individuals with both bilateral and unilateral retinoblastoma. Each family has its own experience with the disease and will have different counseling needs. The genetic counseling process allows for the assessment of the family's risk for a heritable mutation in RB1. This assessment includes a detailed, 3-generation family history (pedigree), as well as a careful review of the medical records of the individual with retinoblastoma, including pathology reports and an evaluation of developmental status. Before undergoing genetic testing, the genetic counselor must explain the benefits and limitations of such testing to the family. Limitations could include the rare occurrence of uninformative results or mosaicism (in which only a portion of the blood cells carry an alteration in the RB1 gene). Once results from genetic testing are received from the lab, a careful review of these results with the family is essential for the understanding of the implications of the test for all involved. Whether a heritable RB1 mutation is found or not, genetic counseling will provide support for the families to process and incorporate this new information. Individuals with normal results in blood, although this reduces the risk for heritable retinoblastoma, will still have a small residual risk for an undetected RB1 mutation, and this will be an important topic of discussion in a genetic counseling session. If an individual has a detectable RB1 mutation, subsequent genetic counseling will involve testing of first-degree family members including healthy parents and siblings.

While genetic counseling and genetic testing for retinoblastoma can be a complicated and unexpected element in the diagnosis and treatment of this disease, it is an integral part of the process. The goal of genetic counseling is to identify those individuals who have a heritable mutation in RB1 and to inform families of the implications of this finding. The test results allow us to focus high-risk screening on those who carry a heritable mutation, and provide reassurance to individuals with sporadic, non-hereditary retinoblastoma. If a mutation is identified, risks to that individual and their family members can be clarified, and unnecessary examinations under anesthesia can be avoided in younger relatives who do not carry the mutation. Genetic testing also has implications for the future offspring of an individual with retinoblastoma and allows timely discussion of screening and treatment options for offspring that may be at risk.