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By
Sharon E. Plon,
M.D., Ph.D., and
Claire Noll, C.G.C
Retinoblastoma has served as the model tumor that has taught us
so much about cancer genetics. We discuss here what we have
learned about the genetics of retinoblastoma and some of the
genetic terms we use.
To start with, retinoblastoma is a monogenic disorder – it is
associated with mutations in a single gene, namely RB1. In terms
of heredity, it is autosomal. This means that men and women are
equally likely to inherit a mutation in RB1 and equally likely
to pass on a mutation. Transmission occurs in a dominant
fashion; that is, a mutation in one copy of the RB1gene is
sufficient to cause an increased risk of the disease in the
child. However, the condition exhibits incomplete penetrance: not everyone that carries a mutation in RB1 develops
retinoblastoma. The penetrance is about 90 percent. If a parent
carries an RB1 mutation there is a 50 percent risk for each
child to inherit the mutation and a 45 percent risk (90 percent
of 50 percent) that they will develop retinoblastoma.
Retinoblastoma also exhibits reduced expressivity: Occasionally
a benign tumor (a retinocytoma) develops that can regress and
leave only a scar. That's why we recommend that both parents of
any child diagnosed with retinoblastoma have a dilated eye exam.
Parents found to have a retinocytoma have an increased risk of
having another child with retinoblastoma. Probably most
importantly, retinoblastoma has a high rate of new or de novo
mutations. In other words, most children who inherit an RB1
mutation and develop retinoblastoma are the first family member
with the disease because the mutation in the RB1 gene may have
occurred in either the egg or the sperm prior to conception.
Alternatively in sporadic retinoblastoma, the first mutation in
the RB1 gene occurs sometime during the development of the eye.
Although the condition is transmitted as a dominant trait, it
behaves as a recessive disorder on the level of the single cell.
Both copies of the gene must be knocked out before a retinal
cell transforms into a retinoblastoma. This is the basis of
Knudson’s two-hit hypothesis of tumor development.
In the hereditary form of retinoblastoma, the first mutation is
found in either the egg or the sperm. The child carries an RB1
mutation in every cell of his or her body. If another RB1 mutation
occurs in a retinal cell early in development, that cell can no
longer function normally and retinoblastoma develops. Because
this mutation happened in a single cell, it is called a somatic
mutation and is sometimes referred to as the “second hit.”
Essentially all children with bilateral retinoblastoma have
inherited an RB1 mutation. However, it is important to remember
that the opposite is not always true. About one in six children
with unilateral retinoblastoma also have the hereditary form.
Because of the hereditary nature of retinoblastoma, it is very
important to screen the siblings of any child with
retinoblastoma – especially if it is bilateral retinoblastoma –
for the disease in order to detect the tumors at a stage when
they can be more easily treated in order to prevent enucleation
or metastatic spread of the disease. This type of screening
often requires eye exams under anesthesia every three to four
months during the first few years of life.
Children with the inherited form of retinoblastoma have a high
risk of developing other cancers later in life. During
childhood, these children have an increased risk of developing
sarcomas, particularly osteosarcoma. In adulthood, they have an
increased risk of developing a variety of tumors including
breast cancer, melanoma and lung cancer. The overall risk of
cancer is higher if they were treated with radiation therapy. We
recommend that all children with hereditary retinoblastoma have
a yearly follow-up exam looking for any evidence of a second
cancer.
Genetic testing for mutations in the RB1 gene is now available
in several laboratories. Many different types of mutations are
known to occur in the RB1 gene, so genetic testing should
optimally include several laboratory methods including DNA
sequencing and detection of deletions or rearrangements of the
gene. For children with bilateral disease, the laboratory
studies a blood sample to identify the inherited RB1 mutations.
For children with unilateral disease, it is optimal to send a
sample of the retinoblastoma tumor as well as a blood sample for
testing. The laboratory first identifies mutations in the tumor,
and then checks the blood to see if they were inherited or only
occurred as the eye developed. If genetic testing of a child
with retinoblastoma identifies the inherited RB1 mutation then
this information can be used to test other family members
to determine if they need to be screened for retinoblastoma.
In about 5 percent of cases,
retinoblastoma can be associated with loss or interruption of
the gene due to a structural chromosome defect, such as a
translocation or chromosomal deletion, which may be seen by
routine karyotype or chromosome analysis. In such cases, the
child may also show developmental delay and other congenital
anomalies. For most children with
retinoblastoma, the mutation will only be identified in a
laboratory specifically studying the RB1 gene.
Finally, remember that mutation testing is not perfect. In some
people, the results of all tests remain negative. In these
cases, additional information, including family history and
clinical presentation, must be used to address the individual’s
risk for additional cancers as well as the risk to his or her
offspring. For more information, refer to
Shedding Light on Retinoblastoma.
- Children with bilateral
retinoblastoma have inherited a mutation in the RB1 gene. This
mutation may be carried by one of the parents, but more often
occurred in the egg or sperm prior to conception.
-
About one in six children with unilateral retinoblastoma also
have the hereditary form of the disease and carry an RB1
mutation.
- Siblings of
children with retinoblastoma should be screened by careful eye
examination every three to four months until age 4.
-
Children with the inherited form of retinoblastoma, including
bilateral cases, have an increased risk of developing second
cancers later in life and should be followed carefully.
-
Genetic testing is becoming available to help aid us in
counseling parents as to their risk of having another child with
retinoblastoma and identifying which members of the family are
at increased risk.
Sharon Plon, M.D., Ph.D., is the chief of
Texas Children's Cancer Center's Cancer Genetics Clinic,
chief of
Texas Children's Neurofibromatosis Clinic and associate professor of pediatrics and director
of the
Medical Scientist Training Program
at Baylor College of
Medicine. Claire Noll is a certified genetics counselor at Texas
Children’s Cancer Center.
Dr. Plon and her team are working
diligently to identify genes that when mutant result in an
increased predisposition to cancer. Other translational research
projects under way in the lab focus on genetic syndromes that
predispose to cancer or bone marrow failure including Fanconi
Anemia and Rothmund-Thomson Syndrome. |
