Thursday 30 June 2011

TP53 and Li Fraumeni Syndrome

George was diagnosed with this first cancer, (embryonal rhabdomyosarcoma in the left temporalis muscle), on his second birthday. That was at Great Ormond Street Hospital, and it had taken us a long time to get him there. His mother, Gina, had died of metastatic ovaria cancer just ten months previously. Part of the delay in getting him diagnosed was the assumption that we were just being paranoid. The odds of him getting cancer so soon after his mother had died of it were assumed to be astronomical. When the diagnosis was finally made we were all stunned. Was it something to do with his mother’s illness? The doctors assured us that this was an unlucky (way, way, way unlucky) coincidence.

Fast forward to George at 15, and the discovery of a basal cell carcinoma during a routine and unrelated visit to the doctor. A second cancer, completely unrelated to what he had as a child. This time the explanation was that it was most likely a long term side-effect of the radiotherapy he had as a child.

Only a few months later George was diagnosed with osteosarcoma in the right side of his jaw (the mandible to be exact). A third cancer, and it had taken many weeks of going from doctor to doctor, hospital to hospital, to get it diagnosed, even though we knew there was something seriously wrong. How could it be that my son had three different cancers? One hypothesis at the time was that like the basal cell carcinoma, the osteosarcoma was a long term side effect of radiotherapy. However, the mystery was finally solved after having a genetic test of his TP53 gene. This is an important tumour suppressor gene, and in his case he had a specific defect that identified him as having classical Li Fraumeni Syndrome (LFS). Once his test result came in other members of the family were also tested and found to be not carrying the mutation – making it most likely that it came from his mother after all.

If he had been tested as a two year old would it have made a difference? Possibly not, but perhaps we would have been spared the delays in getting him diagnosed. We’ll never know. But at the time of his osteosarcoma diagnosis the rules governing who got tested were incredibly complicated. Even the diagnosis of a second cancer wasn’t enough to trigger a test. If we had known George had LFS then I suspect that the osteosarcoma diagnosis would have happened more quickly, and treatment started earlier in the disease.

Thankfully, a visit to the Institute of Cancer Research last week brought some good news. Professor Nazneen Rahman and her colleagues at the ICE Genetics and Epidemiology unit have come up with  a much simplified testing and management protocol for TP53. The key points are that a test should be triggered by the following conditions:

An individual with:
  • Adrenocortical cancer at any age
  • Choroid plexus cancer at any age
  • Rhabdomyosarcoma below 5 yrs
  • Breast cancer below 30 yrs (if eligible for BRCA1/2 testing, this should be performed first)
  • Two or more primary cancers of the following: sarcoma, breast, brain, adrenocortical or any childhood cancer; at least one below 46 yrs

Two relatives affected with:
  • Sarcoma, breast, brain, adrenocortical or any childhood cancer; one relative below 36 yrs and one relative below 46 yrs

Three relatives affected with:
  • Sarcoma below 45 yrs and
  • any cancer below 45 yrs and
  • any cancer below 45 yrs or sarcoma at any age

Under these new criteria it would have been clear that George should have been tested at the age of two. We will never know what difference that information might have made, but at least there would have been more of a willingness to consider cancer early when presenting with unexplained symptoms.

Professor Rahman was also at pains to point out that not all TP53 defects are as dangerous as Li Fraumeni Syndrome, there are some defects which carry much lower risks of getting cancer than LFS. However, this is an area that needs much more research.

From our perspective it’s important that this new testing and management protocol gets as widely adopted as possible. For more details please see:

TP53 Testing and Management Protocol

TP53 Testing and Management Protocol - FAQ


If you are the parent of a child that meets the above criteria, or an adult who fits the bill, please show this protocol to your oncologist. At the very least you can have a discussion about whether to have the test or not.
 

No comments:

Post a Comment