How DNA and Genetic Knowledge Changes Lives: the impact of genetic testing for five families affected by retinoblastoma

Saturday April 22, 2018

For World DNA Day, Retinoblastoma survivor and WE C Hope co-founder / CEO, Abby White, considers the central importance of DNA and genetic knowledge in caring for the child and family, during treatment and throughout life.

Tree of Life - thr trunk of the tree is a DNA double helix

What is DNA?

DNA, or deoxyribonucleic acid, is the hereditary, self-replicating chemical that carries genetic information in humans and most living organisms. DNA is the main material in chromosomes, which we inherit from our mother and father. A gene is a strand of DNA that contains a particular genetic code. Nearly every cell in the body has the same DNA. You could think of DNA as the body’s instruction manual, chromosomes as the chapters within that manual, and genes as the individual detailed sections – the instructions would not exist without the entire manual holding them together.

Why is DNA Important in Retinoblastoma?

Retinoblastoma is caused by changes to the RB1 tumour suppressor gene or MYCN oncogene. All children who have bilateral retinoblastoma, and about 15% of children with unilateral retinoblastoma have a constitutional RB1 mutation that can be inherited. This is classified H1 in the TNMH retinoblastoma staging system.  People who are H1 also have a lifelong higher risk of second primary cancers.

About 50% of children with retinoblastoma are H0, meaning their cancer is not caused by a heritable RB1 mutation.  Genetic testing is the only way to identify whether a person with unilateral retinoblastoma is H1 or H0.

Studying the RB1 and MYCNA genes in tumour and / or blood can pinpoint the specific changes in the individual, guiding patient care and research.  Research of these genes and others involved in retinoblastoma development helps us understand how the cancer forms and responds to treatment.  The findings guide new diagnostics, treatments and genetic tests, and ultimately better experiences for those of us affected by this cancer.

Genetic testing is valuable for affected children, adult survivors and unaffected relatives. Testing must begin with the person who has retinoblastoma (the proband) and expands out to other relatives. Results inform patient care, identify at risk family members, enable family planning and eliminate risk for infants who would otherwise require frequent screening eye exams under general anaesthetic.

To explore the impact of genetic knowledge in retinoblastoma care, I’d like to introduce you to five people diagnosed with this cancer – Alice, Jamie, Megan, Rachel and Peter. We’ll meet each of them in turn and find out how genetic testing can influence treatment, care of family members, lifelong care, and family planning.

DNA was the first three-dimensional xerox machine


When Alice was diagnosed with unilateral retinoblastoma Group D (cT2a) at 9 months, her doctors and parents were very concerned that her young age indicated a risk to her other eye.  She began chemotherapy with the goal of saving her affected eye; primarily because her parents wanted to feel they had tried all options to save her sight, and partly because of concern that her healthy eye might develop cancer.

Genetic testing revealed that Alice did indeed have a constitutional RB1 mutation. This is known as H1 in the TNMH retinoblastoma staging system.  By 18 months of age, Alice’s right eye remained free of cancer, but various forms of chemotherapy failed to control the cancer in her left eye.  Her parents opted to enucleate (surgically remove) her left eye rather than expose her to radiation and further treatments that could increase her lifelong risk of second primary cancers.

Alice’s doctors reassured her parents that very close monitoring would ensure any tumours in her right eye would be found at their earliest stage. They could be treated with minimally invasive therapies, compared to her left eye which was filled with advanced cancer at diagnosis.

When Alice was diagnosed, her 30 month old brother, Jack, began EUAs to check his eyes for signs of cancer.  Once genetic testing found Alice’s exact mutation, blood was taken from Jack and their parents to look for the same mutation. Testing found no mutation in either parent or Jack.  This confirmed Jack’s risk for retinoblastoma is no higher than the general population, he was H0, and he needed no more EUAs. This was a great relief to the children’s parents, and to Jack!

There is a very small possibility (below 1%) that one of the parents has a mutation in only some of their cells (called “mosaic”) that could not be detected with current technology.  This may also reduce the associated lifelong cancer risk.  The parents of Alice and Jack need no special follow up care, but they are now aware and can inform healthcare providers of the RB1 genetics in their family should they have concerning unexplained symptoms.

Today Alice is a spunky, clever schoolgirl who enjoys gymnastics and ice skating.  Her right eye did not develop any tumours and continues to have excellent vision.


Jamie was diagnosed with unilateral retinoblastoma Group E (cT2b) at 22 months. His eye was enucleated several days after diagnosis. Samples of tumour and blood were sent for genetic testing.  Both RB1 gene mutations were found in the tumour, but neither mutation was present in Jamie’s blood sample.  Because the testing lab reports greater than 95% ability to identify mutations for retinoblastoma, the negative test reduced Jamie’s risk of an unidentified mutation to less than 1%.

This result dramatically enhanced Jamie’s quality of life because monitoring his healthy eye could be done without anaesthetic.  This was a relief as he often struggled with the mask and waking up. Doctors explained that the risks posed by general anaesthesia outweigh the tiny chance of a tumour developing in his unaffected eye.  With good child life support, Jamie transitioned to less frequent office exams.  His parents did have to advocate loudly for the child life support through the transition process, but they feel it was worthwhile to avoid the unnecessary EUAs.

When Jamie was diagnosed, his 4 month old twin sisters began EUAs and his 4 year old brother had an office exam to check for signs of Retinoblastoma. Genetic testing found no RB1 mutation in Jamie’s tumour or blood.  There is a very small possibility (below 1%) Jamie has a mosaic mutation that could not be detected with current technology, but mosaic mutations are not inherited.  The test showed that Jamie’s parents and siblings are H0, with only population risk of retinoblastoma.  This information was a great relief to the family, marking an end to the experience of supporting their three youngest children through general anaesthesia on the same day.

When Jamie grows up, his own children can be tested for the mutations of his original eye tumor. Though very unlikely, if testing finds a child to be H1, treatment can begin before tumors are large or dangerous.


Megan was diagnosed with unilateral retinoblastoma Group E (cT3) at 3 months old. Her parents were keen to try to save her eye, but doctors counselled them on the risks of doing so.  Concerned by the advanced stage of cancer at her very young age, doctors suspected Megan may have a very rare, highly aggressive form of retinoblastoma.  Surgical removal of her eye and genetic testing of her tumour would be the only way to confirm this. If their theory was correct, attempts to save her eye would put her life at risk.

Megan’s parents agreed that her eye should be removed to protect her life and to enable thorough genetic testing.  This proved to be a very good decision because pathology examination of her eye found microscopic cancer cells had already invaded her optic nerve – the conduit to her brain. She immediately began 6 months of chemotherapy to kill any cancer cells that had escaped, and save her life.

Extensive analysis of Megan’s tumour found no RB1 mutations.  However, multiple copies of the MYCN oncogene were present, confirming the doctors’ suspicions – Megan had RB1+/+MYCNA retinoblastoma.

In “RB1+/+MYCNA”, the +/+ indicates both copies of the RB1 gene are normal. The “A” stands for Amplification (too many copies) of MYCN.

Amplification of the MYCN gene is most commonly associated with high risk, poor outcome neuroblastoma.  All children with MYCNA retinoblastoma have one tumour in one eye that is highly aggressive and becomes very dangerous at a young age.  Children of the same age with RB1 mutation, usually have much smaller tumours at diagnosis.  Average age at diagnosis of MYCNA retinoblastoma is 4.5 months, and the risk for a baby diagnosed unilateral at 6 months old or younger is 20%; the younger the baby, the more likely they are to have this form of retinoblastoma.

The pathology results gave Megan’s parents peace about their decision to remove her eye, although the treatment she endured to protect her life was a long, hard journey for the young family.  They were thankful her doctors had connected her clinical presentation with the possible genetic subtype, aware of how differently her story could have unfolded had they attempted to save her eye.  Genetic testing confirmed she had no lifelong cancer risk, and needed no screening for her healthy eye – a ray of light along the difficult road of chemotherapy.

Megan is an only child. Her parents always planned to have a big family, but worried about their risk for retinoblastoma after the diagnosis.  Genetic testing confirmed that neither Megan’s children nor any of her future siblings would have an increased risk for retinoblastoma.  Her parents were free to increase their family with confidence.

Today, Megan is a happy, healthy preschooler who loves princesses and everything sparkly.  She will also soon be a big sister.


Rachel was diagnosed with bilateral retinoblastoma at 11 months. Her 3 siblings underwent regular EUAs and awake eye exams until age 6, though none of them developed any tumours.

Years later, extensive genetic testing when Rachel was first pregnant found no RB1 mutation.  Yet Rachel had bilateral retinoblastoma – she definitely must have a constitutional mutation.  The lab’s high test sensitivity suggested Rachel would have a mosaic mutation that could not be detected with technologies available at the time of testing.

The result eliminated risk for her parents and siblings, since mosaic mutations occur at or after conception and cannot be inherited.  This was a particular relief for Rachel’s older sister, for whom the burden of worry about retinoblastoma and second cancers, and not knowing her family’s true risk, weighed very heavy.

Had this highly sensitive genetic testing been available when Rachel’s siblings were children, they and their children would have avoided a total of 40+ EUAs and office exams between them.

Now 30 years old and pregnant with her third child, Rachel recently had a second round of genetic testing. Technologies have advanced significantly in the ten years since her first test, and the progress made all the difference.  An RB1 mutation was found in just 5% of Rachel’s cells, while 95% of her cells have fully functioning copies of the RB1 gene.

The result enabled testing of Rachel’s two children and her unborn baby.  None of them carry the mutation that had caused her retinoblastoma. This is very significant for Rachel. Her younger son no longer needs eye exams, and her new baby will need no eye screening. None of her children will have lifelong concerns about second cancers.  Rachel says the best things come in threes, and in her third pregnancy, she can look forward to raising a baby without worrying about eye exams or cancer.

Retinoblastoma care teams have a responsibility to make genetic counselling and testing available to all families. It adds critical insight to medical care, increases patient safety, arms survivors and their families with knowledge to advocate for their health, and eliminates risk for unaffected relatives.


Peter was diagnosed with unilateral retinoblastoma at 13 months. His eye was immediately removed and he had no other treatment.  Peter grew up thinking he’d escaped pretty lightly until he joined a social networking group and met many other people with retinoblastoma. In the group, he began to hear about second cancers and genetics.  He asked his doctor for referral to a genetic counsellor, who explained the possible scenarios he could be facing, and arranged genetic testing.

Peter was 23 when genetic testing identified a constitutional RB1 mutation (H1). The result confirmed a higher lifelong risk of second primary cancers, and a 50/50 risk of inheriting the mutation for each of his children.

Peter was shocked by the news because he’d grown up believing his cancer was a chance “thing” that would not affect him for life, or have implications for his future family.  The genetic counsellor connected him to a lifelong care clinic for people with increased cancer risk. Conversations with the genetic counsellor and the lifelong care clinic helped educate him about his specific risk.

He learned the importance of avoiding radiation exposure wherever possible, and making healthy lifestyle choices to minimize his risk of developing other cancers.  Navigating health care hasn’t been easy, especially as he encounters many doctors who don’t understand the lifelong implications of retinoblastoma H1. But his personal knowledge has enabled him to be a stronger advocate.

When Peter and his wife, Ruth, were expecting their first child, prenatal genetic testing found their son had inherited Peter’s RB1 mutation.  They elected to deliver Max at 36 weeks gestation to examine his eyes and begin treatment at the earliest opportunity.  Max arrived without incident and an eye exam at birth found four tiny tumours in his left eye. Weekly EUAs captured multiple new tumours across both eyes, all of which were controlled by laser and cryotherapy alone. At 6 months old, Max had several rounds of chemotherapy due to a particularly resistant tumour close to his centre of vision.

Early delivery, frequent EUAs and prompt treatment ensured Max’s retinoblastoma was well controlled. Despite having multiple tumours across both eyes, very close to his macula, he has excellent vision today at 3 years old.

Peter and Ruth desperately wanted a second child, but they didn’t want their baby to endure early delivery, countless EUAs, treatments and lifelong worries about cancer.  So they chose to conceive with the help of Pre-implantation Genetic Diagnosis (PGD).  PGD is a genetic screening process that takes place during in-vitro fertilization (IVF).

After the couple’s embryos were created by uniting the egg and sperm, they were cultured in a lab.  When 5-6 days old, a single cell was removed for genetic testing.  PGD identified which embryos had Peter’s RB1 mutation and which did not. An embryo known to be free of the RB1 mutation was then transferred to Ruth’s womb, and others were frozen for future use.

Peter and Ruth are now happily expecting their second child, knowing eye cancer will not be a part of their baby’s life.  Max need only teach his little brother or sister about the everyday adventures of childhood.

Knowledge, Experience, Understanding and Attitudes

What do parents and survivors know and understand about retinoblastoma genetics?  What’s their experience of genetic counselling and genetic testing, and what concerns and suggestions do they have to improve the process?  Canadian researchers have been working hard to answer these questions, and more.  Here’s a video reporting some of their findings, as their research continues.  Similar studies around the world will gather valuable insight to help enhance care, during retinoblastoma and throughout life.

About the Author

Abby White’s father was diagnosed with bilateral retinoblastoma in Kenya in 1946, and treated in England. Abby was also born with cancer in both eyes. She has an artificial eye and limited vision in her left eye that is failing due to late effects of radiotherapy received as a baby.

Abby studied geography and development in sub-Saharan Africa at university. She co-founded WE C Hope with Brenda Gallie, responding to the needs of one child in Africa, and the desire to help many around the world who seek knowledge, effective medical care and compassionate support.

Abby enjoys listening to audio books, writing, open water swimming and long country walks.


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